EP3039020B1 - Ido inhibitors - Google Patents

Ido inhibitors Download PDF

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Publication number
EP3039020B1
EP3039020B1 EP14766038.5A EP14766038A EP3039020B1 EP 3039020 B1 EP3039020 B1 EP 3039020B1 EP 14766038 A EP14766038 A EP 14766038A EP 3039020 B1 EP3039020 B1 EP 3039020B1
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EP
European Patent Office
Prior art keywords
optionally substituted
alkyl
biphenyl
tetrazol
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP14766038.5A
Other languages
German (de)
French (fr)
Other versions
EP3039020A1 (en
Inventor
Jay A. Markwalder
Steven P. Seitz
James Aaron Balog
Audris Huang
David K. Williams
Libing Chen
Sunil Kumar MANDAL
Shefali SRIVASTAVA
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Publication of EP3039020A1 publication Critical patent/EP3039020A1/en
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Publication of EP3039020B1 publication Critical patent/EP3039020B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates generally to compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and their use in methods of treating proliferative disorders, such as cancer, viral infections and/or autoimmune diseases utilizing the compounds of the invention.
  • IDO indoleamine 2,3-dioxygenase
  • Tryptophan is an amino acid which is essential for cell proliferation and survival. It is required for the biosynthesis of the neurotransmitter serotonin, the synthesis of the cofactor nicotinamide adenine dinucleotide (NAD), and is an important component in the immune system response ("immune escape") to tumors. Depletion of levels of tryptophan is associated with adverse effects on the proliferation and function of lymphocytes and diminished immune system response.
  • NAD cofactor nicotinamide adenine dinucleotide
  • IDO indoleamine-2,3-deoxygenase
  • IDO catalyzes the initial, rate-limiting step in the conversion of tryptophan to N-formylkynurenime.
  • IDO has been implicated in neurologic and psychiatric disorders including mood disorders as well as other chronic diseases characterized by IDO activation and tryptophan degradation such as viral infections, for example, AIDS, Alzheimer's disease, cancers including T-cell leukemia and colon cancer, autoimmune diseases, diseases of the eye such as cataracts, bacterial infections such as Lyme disease, and streptococcal infections.
  • an agent which is safe and effective in inhibiting the function of IDO would be an important addition for the treatment of patients with diseases or conditions affected by the activity of the enzyme.
  • the present invention provides compounds and/or pharmaceutically acceptable salts thereof, stereoisomers thereof or tautomers thereof, their use in methods of modulating or inhibiting the enzymatic activity of IDO, and their use in methods for treating various medical conditions using said compounds.
  • the present invention also provides processes and intermediates for making the compounds of the present invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof.
  • the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and one or more of the compounds of the present invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof.
  • the compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof may be used in the treatment and/or prophylaxis of multiple diseases or disorders associated with enzymatic activity of IDO inhibition, such as cancer, viral infections, autoimmune diseases, and other maladies.
  • the compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof may be used in therapy.
  • the compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof may be used for the manufacture of a medicament for the treatment and/or prophylaxis of multiple diseases or disorders associated with enzymatic activity of IDO.
  • the compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof can be used alone, in combination with other compounds of the present invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof, or in combination with one or more other agent(s).
  • the present invention provides compounds of Formula (I) wherein:
  • the invention provides a compound of Formula (I) within the scope of the first aspect wherein:
  • the invention provides a compound of Formula (I) within the scope of the first or second aspect wherein is phenyl or a 5- to 6-membered monocyclic heteroaryl, and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of Formula (I) within the scope of the first, second or third aspect wherein is: and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound of Formula (F) within the scope of the first, second, third or fourth aspects wherein:
  • the invention provides a compound of Formula (I) within the scope of any of the first to fifth aspects set out above wherein:
  • the invention provides a compound of Formula (I) within the scope of any of the first to sixth aspects set out above wherein:
  • the invention provides a compound of Formula (II) wherein:
  • the invention provides a compound of Formula (II) within the scope of the eighth aspect wherein:
  • the invention provides a compound selected from the exemplified examples within the scope of the previous aspects, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the invention provides a compound selected from any subset list of compounds within the scope of any of the above aspects.
  • the compounds of the invention have human IDO IC 50 values :::;1500 nM.
  • the compounds of the invention have human IDO IC 50 values ⁇ 250 nM.
  • the compounds of the invention have human IDO IC 50 values ⁇ 50 nM.
  • the compounds of the invention have human IDO IC 50 values ⁇ 20 nM.
  • the compounds of the invention have human IDO IC 50 values ⁇ 10 nM.
  • the present invention provides a composition comprising one or more compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • the present invention provides a process for making a compound of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • the present invention provides an intermediate for making a compound of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • the present invention provides one or more compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof for use in a method for the treatment and/or prophylaxis of various types of cancer, viral infections and/or autoimmune diseases, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of one or more compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent, such as a chemotherapeutic agent or a signal transductor inhibitor.
  • a chemotherapeutic agent or a signal transductor inhibitor
  • the present invention provides a compound of the present invention, and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, for use in therapy.
  • the present invention provides a combined preparation of a compound of the present invention, and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.
  • the present invention provides a combined preparation of a compound of the present invention, and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of multiple diseases or disorders associated with the enzymatic activity of IDO.
  • the invention provides a compound described herein and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof for use in a method of treating a patient suffering from or susceptible to a medical condition that is sensitive to enzymatic activity of IDO.
  • a number of medical conditions can be treated.
  • the method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound described herein and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof.
  • the compounds described herein may be used to treat or prevent viral infections, proliferative diseases (e.g ., cancer), and autoimmune diseases.
  • the compounds and pharmaceutical compositions of the present invention are useful in treating or preventing any disease or conditions that are sensitive to enzymatic activity of IDO. These include viral and other infections (e.g ., skin infections, GI infection, urinary tract infections, genito-urinary infections, systemic infections), proliferative diseases (e .g., cancer), and autoimmune diseases (e.g., rheumatoid arthritis, lupus).
  • the compounds and pharmaceutical compositions maybe administered to animals, preferably mammals (e.g ., domesticated animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration may be used to deliver the compound or pharmaceutical composition to the patient. In certain embodiments, the compound or pharmaceutical composition is administered orally. In other embodiments, the compound or pharmaceutical composition is administered parenterally.
  • Compounds of the invention can modulate activity of the enzyme indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • modulate is meant to refer to an ability to increase or decrease activity of an enzyme or receptor.
  • compounds of the invention can be used in methods of modulating IDO by contacting the enzyme with any one or more of the compounds or compositions described herein.
  • compounds of the present invention can act as inhibitors of IDO.
  • the compounds of the invention can be used to modulate activity of IDO in cell or in an individual in need of modulation of the enzyme by administering a modulating (e.g., inhibiting) amount of a compound of the invention.
  • Compounds of the invention can inhibit activity of the enzyme indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • the compounds of the invention can be used to inhibit activity of IDO in cell or in an individual in need of modulation of the enzyme by administering an inhibiting amount of a compound of the invention.
  • the present invention further provides methods of inhibiting the degradation of tryptophan in a system containing cells expressing IDO such as a tissue, living organism, or cell culture.
  • the present invention provides a compound of composition provided herein for use in methods of altering ( e.g ., increasing) extracellular tryptophan levels in a mammal by administering an effective amount of a compound of composition provided herein. Methods of measuring tryptophan levels and tryptophan degradation are routine in the art.
  • the present invention further provides a compound or composition recited herein for use in methods of inhibiting immunosuppression such as IDO-mediated immunosuppression in a patient by administering to the patient an effective amount of a compound or composition recited herein.
  • IDO-mediated immunosuppression has been associated with, for example, cancers, tumor growth, metastasis, viral infection, and viral replication.
  • the present invention further provides a compound of the present invention or a pharmaceutical composition thereof for use in methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of IDO in an individual (e.g ., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof.
  • Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the IDO enzyme, such as over expression or abnormal activity.
  • An IDO-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity.
  • IDO-associated diseases include cancer, viral infection such as HIV infection, HCV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation ( e.g ., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis and systemic lupus erythematosus.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" the IDO enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having IDO, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the IDO enzyme.
  • IDO inhibitor refers to an agent capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) and thereby reversing IDO-mediated immunosuppression.
  • the IDO inhibitor may inhibit IDO1 and/or IDO2 (INDOL1).
  • An IDO inhibitor may be a reversible or irreversible IDO inhibitor.
  • a reversible IDO inhibitor is a compound that reversibly inhibits IDO enzyme activity either at the catalytic site or at a non-catalytic site and "an irreversible IDO inhibitor” is a compound that irreversibly destroys IDO enzyme activity by forming a covalent bond with the enzyme.
  • Types of cancers that may be treated with the compounds of this invention include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leuk
  • the invention provides a a compound or composition of the present invention for use in a method of treating an autoimmune disease by providing to a patient in need thereof a compound or composition of the present invention.
  • autoimmune diseases include, but are not limited to, collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus.
  • Sharp's syndrome CREST syndrome (calcinosis, Raynaud's syndrome, esophageal dysmotility, telangiectasia), dermatomyositis, vasculitis (Morbus Wegener's) and Sjögren's syndrome, renal diseases such as Goodpasture's syndrome, rapidly-progressing glomerulonephritis and membrano-proliferative glomerulonephritis type II, endocrine diseases such as type-I diabetes, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroidism, pernicious anemia, gonad insufficiency, idiopathic Morbus Addison's, hyperthyreosis, Hashimoto's thyroiditis and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa
  • One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g ., IL2 and GM-CSF), and/or tyrosine kinase inhibitors can be optionally used in combination with the compounds of the present invention for treatment of IDO-associated diseases, disorders or conditions.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosourea
  • suitable agents for use in combination with the compounds of the present invention include: dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM.
  • DTIC dacarbazine
  • BCNU carmustine
  • cisplatin the "Dartmouth regimen” which consists of DTIC, BCNU, cisplatin and tamoxifen
  • a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOYTM.
  • Compounds according to the invention may also be combined with immunotherapy drugs, including cytokines such as interferon
  • Antimelanorna vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps.
  • Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.
  • Melanomas that are confined to the arms or legs may also be treated with a combination of agents including one or more compounds of the invention, using a hyperthermic isolated limb perfusion technique.
  • This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects.
  • the fluid is warmed to 102° to 104° F.
  • Melphalan is the drug most often used in this chemotherapy procedure. This can be given with another agent called tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • methotrexate including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
  • certain natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins
  • vinblastine vincristine, vindesine
  • bleomycin dactinomycin, daunorubicin,
  • cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and droloxafine.
  • cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (HERCEPTIN®), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-1O or TGF- ⁇ ).
  • HERCEPTIN® antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1
  • cytokines IL-1O or TGF- ⁇
  • anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.
  • anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • the pharmaceutical composition of the invention may optionally include at least one signal transduction inhibitor (STI).
  • STI signal transduction inhibitor
  • a "signal transduction inhibitor” is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis.
  • Suitable STIs include, but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone: C225 [ Goldstein et al., Clin.
  • ABX-EGF her-2/neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 ( Kohl et al., Nat.
  • FTI farnesyl transferase inhibitors
  • Akt family kinases or the Akt pathway such as, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000 ));
  • cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-O1 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc.
  • At least one STI and at least one IDO inhibitor may be in separate pharmaceutical compositions.
  • at least one IDO inhibitor and at least one STI may be administered to the patient concurrently or sequentially.
  • at least one IDO inhibitor maybe administered first, at least one STI may be administered first, or at least one IDO inhibitor and at least one STI may be administered at the same time.
  • the compounds may be administered in any order.
  • the present invention further provides a pharmaceutical composition for the treatment of a chronic viral infection in a patient comprising at least one IDO inhibitor, optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent, in a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions may include at least one IDO inhibitor of the instant invention in addition to at least one established (known) IDO inhibitor.
  • at least one of the IDO inhibitors of the pharmaceutical composition is selected from the group consisting of compounds of formulas (I) and (II).
  • composition for use in a method for treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.
  • At least one IDO inhibitor and at least one chemotherapeutic agent may be administered to the patient concurrently or sequentially.
  • at least one IDO inhibitor may be administered first, at least one chemotherapeutic agent may be administered first, or at least one IDO inhibitor and the at least one STI may be administered at the same time.
  • the compounds may be administered in any order.
  • any antiviral agent or STI may also be administered at any point in comparison to the administration of an IDO inhibitor.
  • Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV).
  • HCV hepatitis C virus
  • HPV human papilloma virus
  • CMV cytomegalovirus
  • HSV herpes simplex virus
  • EBV Epstein-Barr virus
  • varicella zoster virus coxsackie virus
  • coxsackie virus human immunodeficiency virus
  • the pharmaceutical compositions comprising at least one IDO inhibitor of the instant invention may be administered to a patient to prevent arterial restenosis, such as after balloon endoscopy or stent placement.
  • the pharmaceutical composition further comprises at least one taxane (e.g ., paclitaxel (Taxol); see e.g., Scheller et al., Circulation, 110:810-814 (2004 )).
  • Suitable antiviral agents contemplated for use in combination with the compounds of the present invention can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.
  • NRTIs nucleoside and nucleotide reverse transcriptase inhibitors
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • protease inhibitors and other antiviral drugs.
  • Suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA).
  • ZT zidovudine
  • ddl didanosine
  • ddC zalcitabine
  • stavudine d4T
  • NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B.
  • Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549.
  • Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • kits useful for example, in the treatment or prevention of IDO-associated diseases or disorders, obesity, diabetes and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • the combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g ., surgery or radiation treatment).
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • compositions which comprise a therapeutically effective amount of one or more of the compounds of Formula I, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally, one or more additional therapeutic agents described above.
  • the compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques ( e.g ., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • composition means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day.
  • the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g ., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, e.g ., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • Dosage forms suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • a typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier.
  • compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g ., an anticancer agent or other pharmaceutically active material.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.
  • composition While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • references made in the singular may also include the plural.
  • references made in the singular may also include the plural.
  • “a” and “an” may refer to either one, or one or more.
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form.
  • a free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers.
  • Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
  • substituents are selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl
  • a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 alkyl denotes alkyl having 1 to 6 carbon atoms.
  • Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g ., n-propyl and isopropyl), butyl ( e.g., n-butyl, isobutyl, t -butyl), and pentyl ( e.g ., n-pentyl, isopentyl, neopentyl).
  • alkenyl denotes a straight- or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
  • C 2 -C 8 alkenyl contains from two to eight carbon atoms.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
  • alkynyl denotes a straight- or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
  • C 2 -C 8 alkenyl contains from two to eight carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • alkoxy refers to an -O-alkyl group.
  • C 1-6 alkoxy (or alkyloxy), is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkoxy groups.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy ( e.g ., n-propoxy and isopropoxy), and t -butoxy.
  • alkylthio or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-.
  • aryl either alone or as part of a larger moiety such as “aralkyl”, “aralkoxy”, or aryloxyalkyl” refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to 15 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl refers to an aromatic ring system which includes, but not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and terahydronaphthyl.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl and the like. The fused aryls may be connected to another group either at a suitable position on the cycloalkyl ring or the aromatic ring. For example:
  • cycloalkyl refers to cyclized alkyl groups.
  • C 3-6 cycloalkyl is intended to include C 3 , C 4 , C 5 , and C 6 cycloalkyl groups.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • cycloalkenyl refers to cyclized alkenyl groups.
  • C 4-6 cycloalkenyl is intended to include C 4 , C 5 , and C 6 cycloalkenyl groups.
  • Example cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • cycloalkylalkyl refers to a cycloalkyl or substituted cycloalkyl bonded to an alkyl group connected to the carbazole core of the compound.
  • Halo or halogen includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • haloalkyl also include "fluoroalkyl” that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • C 1-6 haloalkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 haloalkoxy groups.
  • Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.
  • haloalkylthio or “thiohaloalkoxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S-, and pentafluoroethyl-S-.
  • benzyl refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group.
  • heterocycle As used herein, the term “heterocycle,” “heterocyclyl,” or “heterocyclic group” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting ofN, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O) p , wherein p is 0, 1 or 2).
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
  • heterocycle it is intended to include heteroaryl.
  • heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a H -carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2 H ,6 H- 1,5,2-dithiazinyl, dihydrofuro[2,3- b ]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1
  • bicyclic heterocycle or "bicyclic heterocyclic group” is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S.
  • one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring.
  • the second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).
  • the bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
  • bicyclic heterocyclic group examples include quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.
  • aromatic heterocyclic group or "heteroaryl” is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodiox
  • Heteroaryl groups are substituted or unsubstituted.
  • the nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O) p , wherein p is 0, 1 or 2).
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • heterocyclylalkyl refers to a heterocyclyl or substituted heterocyclyl bonded to an alkyl group connected to the carbazole core of the compound.
  • EWG electron withdrawing group
  • EWGs include, but are not limited to, CF 3 , CF 2 CF 3 , CN, halogen, haloalkyl, NO 2 sulfone, sulfoxide, ester, sulfonamide, carboxamide, alkoxy, alkoxyether, alkenyl, alkynyl, OH, C(O)alkyl, CO 2 H, phenyl, heteroaryl, -O-phenyl, and -O-heteroaryl.
  • EWG include, but are not limited to, CF 3 , CF 2 CF 3 , CN, halogen, SO 2 (C 1-4 alkyl), CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , and heteroaryl. More preferred examples of EWG include, but are not limited to, CF 3 and CN.
  • amine protecting group means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent.
  • amine protecting groups fitting these criteria include those listed in Wuts, P. G. M. and Greene, T.W. Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007 ) and The Peptides: Analysis, Synthesis, Biology, Vol.
  • amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert -butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as
  • substituted means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • nitrogen atoms e.g ., amines
  • these may be converted to N-oxides by treatment with an oxidizing agent (e.g ., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
  • an oxidizing agent e.g ., mCPBA and/or hydrogen peroxides
  • shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N ⁇ O) derivative.
  • any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.
  • R is selected independently from the definition of R.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Allen, L. V. Jr., Ed.; Pharmaceutical Press, London, UK (2012 ), the disclosure of which is hereby incorporated by reference.
  • compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention.
  • a prodrug within the scope and spirit of the invention.
  • Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
  • Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se.
  • Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood.
  • physiologically hydrolyzable esters of compounds of formula I include C 1-6 alkyl, C 1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C 1-6 alkanoyloxy-C 1-6 alkyl (e.g ., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C 1-6 alkoxycarbonyloxy-C 1-6 alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts.
  • esters may be prepared by conventional techniques known in the art. Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2nd edition, reproduced, 2006 ); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003 ); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, 3rd edition, Academic Press, San Diego, CA (2008 ).
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • solvate means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
  • the term "patient” refers to organisms to be treated by the methods of the present invention.
  • Such organisms preferably include, but are not limited to, mammals (e.g ., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably refers to humans.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent, i.e., a compound of the invention, that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. The term also includes within its scope amounts effective to enhance normal physiological function
  • treating includes any effect, e.g ., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • bases include, but are not limited to, alkali metals (e.g ., sodium) hydroxides, alkaline earth metals (e.g ., magnesium), hydroxides, ammonia, and compounds of formula NW 4 + , wherein W is C 1-4 alkyl, and the like.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • the compounds of the present invention may be prepared by methods such as those illustrated in the following Schemes utilizing chemical transformations known to those skilled in the art. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. These Schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein. Different methods may be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s).
  • Scheme 2 describes a preparation of compounds of the invention I similar to that of Scheme 1 but with the transformations performed in a different order.
  • Suzuki or related coupling is performed on intermediate (iii) to afford aniline (v) which is derivatized by reaction with an isocyanate (iva) to afford compounds of the invention I.
  • Scheme 3 illustrates a route to compounds of the invention I in which the Suzuki or related coupling is performed on intermediates (ii) to afford intermediates (vi). Reduction under the conditions described above provides anilines (v) which react with isocyanates to afford compounds of the invention I.
  • Scheme 4 illustrates a method suitable for preparation of compounds of the invention I for which the boronic acid/ester or related derivatives of the group do not readily undergo coupling reactions or are not commercially available or readily accessible.
  • Derivative (iii) can be coupled with boronate ester dimers such as bis(neopentylglycolato)diboron (vii) by heating in a solvent such as DMSO, dioxane, toluene or DMF in the presence of a base such as potassium acetate and a catalyst such as Cl 2 Pd(dppf) to give aryl boronate esters (viii).
  • a solvent such as DMSO, dioxane, toluene or DMF
  • a catalyst such as Cl 2 Pd(dppf)
  • Scheme 6 describes an additional method for the preparation of compounds of the invention I.
  • Esters (xii) may be saponified to the corresponding carboxylic acids (xiii) under various conditions familiar to those of ordinary skill in the art. Generally this is effected using an alkali metal hydroxide (MOH) in aqueous solution, preferably with an organic co-solvent such as methanol or THF.
  • MOH alkali metal hydroxide
  • Carboxylic acids (xiii) can be converted (by treatment with DPPA and a tertiary amine base) to acyl azides which rearrange (Curtius rearrangement) upon heating to form isocyanates which can be trapped by alcohols R'OH to furnish carbamates (xiv).
  • acyl azides which rearrange (Curtius rearrangement) upon heating to form isocyanates which can be trapped by alcohols R'OH to furnish carbamates (xiv).
  • Many variations on the Curtius rearrangement are familiar to those skilled in the art of organic/medicinal chemistry which have utility for the transformation of carboxylic acids such as (xiii) into carbamates (xiv) or the related amines (iii). Transformation of carbamates (xiv) into the corresponding anilines (xii) is effected in a manner which depends upon the nature of the R' group.
  • Scheme 7 describes a preparation of compounds of the invention I similar to that of Scheme 6 in which the intermediate isocyanate formed in the Curtius rearrangement is intercepted by an amine R 9 NH 2 to generate urea intermediate (iv).
  • Intermediate (xv) is further transformed using the Suzuki or related coupling into compounds of the invention I.
  • Scheme 9 describes a preparation of compounds of the invention starting from dibromoaniline or related dihaloheterocycles (xx) where X and Q are each halo.
  • Introduction of the NHCONHR 9 group is accomplished as in the above Schemes to provide dibromourea (xxi).
  • This intermediate can undergo Suzuki or related coupling at the less hindered bromide to afford intermediate (xxii).
  • treatment with amines HNR 7 R 8 and an appropriate catalyst, preferably using the conditions of Buchwald affords compounds of the invention I.
  • Scheme 10 illustrates the conversion of nitriles (xxiii) into tetrazole intermediates (xxiv) which can be converted to compounds of the invention as described herein.
  • the nitrile (xxiii) is prepared by chemistry described above (often Suzuki coupling on an intermediate such as (iii)) and heated with an azide such as tributyltinazide in a solvent such as toluene at or near the boiling point.
  • Compounds (xxiv) may be converted to compounds of the invention I or may be intermediates which are transformed into compounds of the invention I by methods taught in the previous schemes. This methodology could be used to prepare heteroaromatic tetrazole derivatives in addition to the phenyl derivatives shown.
  • the carboxylic acids prepared in Scheme 11 can be derivatized (Scheme 12) to provide acylsulfonamides (xxxii) which may be transformed into compounds of the invention I using chemistry described in the schemes above.
  • acylsulfonamides xxxii
  • the conversion of carboxylic acids to acylsulfonamides is accomplished using a coupling reagent such as CDI and a base such as DBU in a solvent such as DMF or THF.
  • This methodology could be used to prepare heteroaromatic acylsulfonamide derivatives in addition to the phenyl derivatives shown.
  • Air- or moisture-sensitive reactions were generally performed under an atmosphere of nitrogen or argon in anhydrous solvents (EMD DRISOLV®).
  • Zinc (-325 mesh) for nitro group reduction was obtained from Alfa Aesar. Reaction concentrations indicated in the tables and procedures are given in units of molar and are approximate. Temperatures are given in degrees Celsius. Reactions were monitored for completeness by thin layer chromatography (TLC) or tandem liquid chromatography-mass spectroscopy (LCMS).
  • TLC thin layer chromatography
  • LCMS tandem liquid chromatography-mass spectroscopy
  • “dried” refers to the addition of anhydrous MgSO 4 followed by filtration and rinsing the residual solids with an appropriate organic solvent.
  • “Stripped” means concentration under reduced pressure, generally on a rotary evaporator.
  • “Silica gel chromatography”, “flash chromatography”, or “chromatographed on silica gel” refers to glass column chromatography performed in a manner similar to that described by Still (J. Org. Chem., 43:2923 (1978 )). Typically silica gel 60 (EMD, 230-400 mesh ASTM) is used with solvents from JT Baker or Mallinckrodt.
  • HPLC refers to purification by reverse-phase high-performance liquid chromatography generally on C18 columns using the stated mobile phases. Analytical HPLC runs were performed using the columns, flow rates, and mobile phases indicated. It is understood that analytical HPLC retention times (T r ) are reported in minutes, and may be dependent on temperature, pH, and other factors. ISCO refers to chromatography on pre-packed silica gel cartridges using automated systems marketed by Teledyne Isco. For all chromatographic purifications the isolation of product by concentration of the appropriate fractions by evaporation at or below ambient pressure is implied. Melting points were determined on a Thomas-Hoover Uni-Melt apparatus and are uncorrected. Generally, mass spectral results are reported as the (M+H) + value.
  • integration intensities, peak shapes, chemical shifts and coupling constants can be dependent on solvent, concentration, temperature, pH, and other factors. Further, peaks which overlap with or exchange with water or solvent peaks in the NMR spectrum may not provide reliable integration intensities.
  • aniline derivatives iii may be made by alkylation of nitroanilines followed by reduction as described above.
  • the procedure below is illustrative.
  • 4-bromo-N1-cyclohexyl-6-fluoro-N1-isobutylbenzene-1,2-diamine was prepared from 5-bromo-1,2-difluoro-3-nitrobenzene and N-isobutylcyclohexanamine by the procedures outlined in the examples above.
  • N-(2-bromophenyl)-1,1,1-trifluoromethanesulfonamide (4A) (189 mg, 0.622 mmol, 36% yield) was obtained as a brown oil.
  • MS(ES): m / z 304 [M-H] - .
  • the vial was evacuated and filled with argon 3x, then heated at 80 °C for 3h, cooled to RT and the contents purified by ISCO Companion (0-20% EtOAc/hexane; 80g column). 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (355 mg, 1.068 mmol, 57% yield) was obtained as a white solid.
  • N-(3'-Amino-4'-(diisobutylamino)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide (30 mg, 0.068 mmol, 41% yield) was obtained as a purple gum.
  • N-(3'-Amino-4'-(diisobutylamino)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide (4C) (30 mg, 0.068 mmol) was taken up in THF (Volume: 2 mL) and 1-isocyanato-4-methylbenzene (0.011 mL, 0.088 mmol) was added. The reaction was stirred at rt overnight, and then solvent removed in vacuo. The reaction mixture was purified by prep.
  • N4,N4-Diisobutyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (7B) (20 mg, 0.055 mmol) was taken up in DCM (1 mL) and Et 3 N (0.038 mL, 0.274 mmol) and 4-nitrophenyl carbonochloridate (13 mg, 0.066 mmol) were added. The reaction was stirred at rt for 1h, an additional 5 eq. of Et 3 N and 1.2 eq. 4-nitrophenyl carbonochloridate were added, and the reaction was stirred overnight. The reaction was diluted with DCM and washed with 0.1M HCl, then brine.
  • N-benzyl-4-bromo-2-nitro-N-(3,3,3-trifluoropropyl)aniline (8B) (0.1 g, 0.248 mmol) in ethanol (6 mL) was added 1 mL of water followed by ammonium chloride (0.199 g, 3.72 mmol). The mixture was stirred 10 min. at RT then treated with zinc (0.243 g, 3.72 mmol). This mixture was stirred 30 min. at RT, diluted with dichloromethane, and filtered.
  • amines RNH 2 and carboxylic acids R'CO 2 H are coupled to give amides which are further transformed by the action of LiAlH 4 into secondary amines RNHCH 2 R' (lx, Table 2) useful as intermediates in the synthesis of compounds of the present invention.
  • Additional secondary amines RNHCHR'R"(lx) useful as intermediates in the synthesis of compounds of the present invention may be prepared by the scheme below. Some Examples prepared by this method are shown in Table 3a.
  • the Example below utilizing sodium cyanoborohydride as the reducing agent and acetic acid as a proton source is representative and not intended to be limiting. Additional proton sources could include any number of inorganic acids such as HCl or HBr and other organic acids.
  • Other reducing agents utilized for this transformation include but are not limited to sodium triacetoxyborohydride and sodium borohydride.
  • amines RNH 2 and aldehydes/ketones R'COR are condensed to secondary amines RNHCHR'R" (lx, Table 3 a) useful as intermediates in the synthesis of compounds of the present invention.
  • Table 3 a Amine Starting Materials Made by Reductive Amination Entry RNH 2 R'COR” (M+H) + T r lxj 196 1.00 p lxk 210 1.18 p lxl 142 (Crude product was derivatized as the t -butyl carbamate for purification, then deprotected to give the desired amine ⁇ HCl.) 1.36 p
  • Additional secondary amines RNHCHR'R"(lx) useful as intermediates in the synthesis of compounds of the present invention may be prepared by the scheme below. Some Examples prepared by this method are shown in Table 3b.
  • amines RNH 2 and aldehydes/ketones R'COR are converted to secondary amines RNHCHR'R" (lx, Table 3b) useful as intermediates in the synthesis of compounds of the present invention.
  • Table 3b Amine Starting Materials Made by Reductive Amination Entry RNH 2 R'COR” (M+H) + T r lxt 200 1.12 p lxu 228 1.02 p lxv 200 0.49 k lxw 226 (M-H) - 1.31 w lxy 224 0.64 s
  • amines RNH 2 are derivatized as t -butyl carbamates, alkylated, and then deprotected to afford secondary amine hydrochloride salts RNHCH 2 R' ⁇ HCl (lx, Table 4) useful as intermediates in the synthesis of compounds of the present invention.
  • Table 5 Bromourea Intermediates Made by Scheme 1 R 9 NR 7 R 8 Temp.
  • aniline intermediates iii and the appropriate isocyanate R 9 NCO are converted to the urea intermediates iv. Table 7 B5F Bromourea Intermediates Made by Scheme 1 Ex. R 9 -NR 7 R 8 Temp. (°C) (M+H) + T r ivca 60 436 5.05 l ivcb 55 4.58 4.22 l ivcc 55 478 3.65 q ivcd 45 482 3.60 q ivce 45 500 3.65 q ivcf 452 5.22 l ivcg 45 490 5.39 l
  • aniline intermediates (iii) and the appropriate isocyanate R 9 NCO are converted to the urea intermediates (iv).
  • Table 8 Ex. R 9 -NR 7 R 8 Temp. (°C) (M+H) + T r ivda 50 482 5.49 l ivdb 50 478 5.59 l ivdc 50 516 5.75 q
  • Examples 280 to 287 were prepared using the method described herein, i.e ., the preparation of 2 from 2A, from aniline intermediates A and the appropriate isocyanates R 9 NCO.
  • Table 15 Ex. No. Name NR 7 R 8 R 9 HPLC Ret Time (M+H) + / (M-1) 280 1-(2-(difluoromethoxy) phenyl)-3-(4-(diisobutyl amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea 19.84 t 550.3 281 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-methoxyphenyl)urea 19.27 t 514.3 282 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-(1,1'-
  • the compound was prepared from N4-benzyl-N4-isobutyl-2'-(2-trityl-2H-tetrazol-5-yl) biphenyl-3, 4-diamine by the general procedure used for the conversion of A to IIA as set out prior to Examples 280 to 287 and followed by detritylation (DCM, TFA, 1 hr).
  • MS(ES): m / z 531.2 [M+H] + , HPLC Tr: 19.8.
  • the compound was prepared from N4-benzyl-N4-isobutyl-2'-(2-trityl-2H-tetrazol-5-yl) biphenyl-3, 4-diamine by the general procedure used for the conversion of A to IIA as set out prior to Examples 280 to 287 and followed by detritylation (DCM, TFA, 1 hr).
  • MS(ES): m / z 602.2 [M+H] + , HPLC Tr: 20.52.
  • reaction mixture was diluted with DCM and washed with water, brine solution, the organic layer dried over Na 2 SO 4 and concentrated to provide 1-(5-bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(4-cyclopropyl-3-fluorophenyl)urea (35 mg).
  • the title compound was prepared from 1-(5-bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(4-cyclopropyl-3-fluorophenyl)urea (296A) as outlined above.
  • reaction was warmed to 50°C overnight then cooled and treated with 100 uL of 5-6 M HCl in isopropanol. This mixture was briefly warmed to 50°C, stirred overnight at RT, then concentrated and partially purified by reverse-phase HPLC (methanol-water gradient +0.1% TFA).
  • This material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.
  • a reaction vial was charged with DMF (5.0 mL), 4-bromo-1-fluoro-2-nitrobenzene (304 mg, 1.382 mmol) and 2-boronobenzoic acid (459 mg, 2.76 mmol). Nitrogen was bubbled through the solution for 20 minutes. A solution of potassium carbonate (2764 ⁇ l, 2.76 mmol) (1.0 M solution) was added and bubbling with nitrogen continued for a few more minutes. Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) was added and the vial was sealed. The reaction was heated to 90 °C for 3 hours. The light orange reaction was cooled and quenched with 10% acetic acid. Some precipitate formed.
  • the reaction was concentrated under a stream of nitrogen. The reaction was filtered and the yellow solid rinsed with water. This first crop contained product but was not pure by TLC on silica gel (1:1 ethyl acetate-hexanes +0.5% acetic acid). After standing, additional solid precipitates from the mother liquor. Filtration provided 4'-fluoro-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (153 mg, 42%) as a pale yellow solid.
  • a reaction vial was charged with 4'-fluoro-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (111 mg, 0.425 mmol), palladium(II) acetate (9.5 mg, 0.042 mmol), silver carbonate (234 mg, 0.850 mmol), lithium carbonate (62.8 mg, 0.850 mmol), t-Boc-L-phenylalanine (22.6 mg, 0.085 mmol), potassium methyltrifluoroborate (155 mg, 1.275 mmol). DMF (32.9 ⁇ L, 0.425 mmol) and a stirring bar. t-Butanol (3.0 mL) was added and the vial was evacuated and filled with nitrogen three times.
  • the vial was sealed, and the reaction was stirred for 5 minutes at ambient temperature. The reaction was then warmed to 90 °C for three days. The cooled reaction was quenched with 2 mL 1 N hydrochloric acid and sonicated. Methylene chloride was added, and the reaction was filtered. The filtrate was transferred to a separatory funnel and partitioned between methylene chloride and water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by RP-HPLC (methanol-water gradient +0.1% TFA).
  • the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5- ⁇ m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 25-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.
  • Part A 1-(2'-cyano-4-(cyclohexyl(isobutyl)amino)-5',6-difluoro-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • the compound was prepared from 1-(2'-cyano-4-(cyclohexyl(isobutyl)amino)-5',6-difluoro-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea by the general procedure used for the conversion of 7A into 7B.
  • MS(ES): m / z 560[M + H] + .
  • Part A 1-((4-bromo-2-nitrophenyl)(cyclohexyl)amino)propan-2-one
  • Part B 4-bromo-N-cyclohexyl-N-(2,2-difluoropropyl)-2-nitroaniline
  • Part C 1-(5-bromo-2-(cyclohexyl(2,2-difluoropropyl)amino)phenyl)-3-(p-tolyl)urea
  • the reaction was stirred 1h at RT.
  • LCMS of the first step indiates that much hydroxylamine intermediate was present.
  • the second step has proceeded to give a mixture of the desired urea and N-hydroxy urea.
  • the reaction was diluted with 2 mL of ethanol and 0.2 mL of water followed by 0.05g of ammonium chloride and 0.1g of zinc.
  • the reaction was stirred ON at RT.
  • the reaction was concentrated and applied to a silica gel column.
  • Part D 4-bromo-N-isobutyl-2-nitro-6-(1-phenylallyl)aniline
  • Part E 4-bromo-N1-isobutyl-6-(1-phenylallyl)benzene-1,2-diamine
  • Part F 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(2-fluorophenyl)urea
  • Part A 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(p-tolyl)urea

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Description

    FIELD OF THE INVENTION
  • The invention relates generally to compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and their use in methods of treating proliferative disorders, such as cancer, viral infections and/or autoimmune diseases utilizing the compounds of the invention.
    • BACKGROUND OF THE INVENTION
  • Tryptophan is an amino acid which is essential for cell proliferation and survival. It is required for the biosynthesis of the neurotransmitter serotonin, the synthesis of the cofactor nicotinamide adenine dinucleotide (NAD), and is an important component in the immune system response ("immune escape") to tumors. Depletion of levels of tryptophan is associated with adverse effects on the proliferation and function of lymphocytes and diminished immune system response.
  • The enzyme indoleamine-2,3-deoxygenase (IDO) is overexpressed in many human tumors. IDO catalyzes the initial, rate-limiting step in the conversion of tryptophan to N-formylkynurenime. Moreover, IDO has been implicated in neurologic and psychiatric disorders including mood disorders as well as other chronic diseases characterized by IDO activation and tryptophan degradation such as viral infections, for example, AIDS, Alzheimer's disease, cancers including T-cell leukemia and colon cancer, autoimmune diseases, diseases of the eye such as cataracts, bacterial infections such as Lyme disease, and streptococcal infections.
  • Accordingly, an agent which is safe and effective in inhibiting the function of IDO would be an important addition for the treatment of patients with diseases or conditions affected by the activity of the enzyme.
    • SUMMARY OF THE INVENTION
  • The present invention provides compounds and/or pharmaceutically acceptable salts thereof, stereoisomers thereof or tautomers thereof, their use in methods of modulating or inhibiting the enzymatic activity of IDO, and their use in methods for treating various medical conditions using said compounds.
  • The present invention also provides processes and intermediates for making the compounds of the present invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof.
  • The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and one or more of the compounds of the present invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof.
  • The compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof may be used in the treatment and/or prophylaxis of multiple diseases or disorders associated with enzymatic activity of IDO inhibition, such as cancer, viral infections, autoimmune diseases, and other maladies.
  • The compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof may be used in therapy.
  • The compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof may be used for the manufacture of a medicament for the treatment and/or prophylaxis of multiple diseases or disorders associated with enzymatic activity of IDO.
  • The compounds of the invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof can be used alone, in combination with other compounds of the present invention and/or pharmaceutically acceptable salts thereof or stereoisomers thereof or tautomers thereof, or in combination with one or more other agent(s).
  • Other features and advantages of the invention will be apparent from the following detailed description and claims.
    • DETAILED DESCRIPTION OF THE INVENTION I. COMPOUNDS OF THE INVENTION
  • In a first aspect, the present invention provides compounds of Formula (I)
    Figure imgb0001
     wherein:
    • W is CR4 or N,
    • V is CR5 or N, and
    • Y is CR6 or N;
    • Figure imgb0002
      is optionally substituted aryl or optionally substituted 5- to 7-membered monocyclic heteroaryl;
    • R1 is COOH, optionally substituted heterocyclyl, -NHSO2R20,
      Figure imgb0003
       -CONHSO2R21, -CONHCOOR22 or -SO2NHCOR23;
    • R2 and R3 are independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy or optionally substituted N(C1-C6 alkyl)2;
    • R4, R5 and R6 are independently H, halogen, CN, OH, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy;
    • R7 and R8 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted di-deutero-C1-C10-alkyl, optionally substituted C2-C10 alkynyl, optionally substituted 5- to 7-membered monocyclic heteroaryl, optionally substituted 8- to 10-membered bicyclic heteroaryl, optionally substituted aryl C1-C6 alkyl, arylsulfonyl, optionally substituted C2-C6 alkenyl, or optionally substituted C5-C8 cycloalkenyl,
    • provided that only one of R7 and R8 is H,
    • or R7 and R8 are taken together with the nitrogen to which they are attached to form an optionally substituted 5- to 10-membered monocyclic or bicyclic heterocyclic ring, or an optionally substituted 5- to 7-membered monocyclic heteroaryl ring;
    • R9 is optionally substituted aryl; optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted 5- to 7-membered monocyclic heterocyclo, optionally substituted 7- to 10-membered bicyclic heterocyclo, optionally substituted 5- to 7-membered monocyclic heteroaryl, optionally substituted 8- to 10-membered bicyclic heteroaryl, optionally substituted C1-C6 alkanoyloxy 5- to 7-membered monocyclic heteroaryl, R24CO-, optionally substituted C1-C6 alkoxy, optionally substituted aryloxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C5-C8 cycloalkenyl;
    • R20 is optionally substituted C1-C6 alkyl, CH2CF3, CF3 or CF2CF3;
    • R21 is optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl;
    • R22 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
    • R23 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
    • R24 is optionally substituted aryl-C1-C6-alkyl, optionally substituted C1-C6 alkylaryl, aryl-C1-C6-alkyl(hydroxy), or optionally substituted C1-C6 alkyl;
    • and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. thereof
  • In a second aspect, the invention provides a compound of Formula (I) within the scope of the first aspect wherein:
    • W is CR4;
    • V is CR5;
    • Y is CR6 or N;
    • R4 is H or halo;
    • R5 is H or halo; and
    • R6 is H or halo;
    • and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • In a third aspect, the invention provides a compound of Formula (I) within the scope of the first or second aspect wherein
    Figure imgb0004
    is phenyl or a 5- to 6-membered monocyclic heteroaryl, and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • In a fourth aspect, the invention provides a compound of Formula (I) within the scope of the first, second or third aspect wherein
    Figure imgb0005
    is:
    Figure imgb0006
    Figure imgb0007
     and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • In a fifth aspect, the invention provides a compound of Formula (F) within the scope of the first, second, third or fourth aspects wherein:
    • R1 is COOH, optionally substituted heterocyclyl, -NHSO2R20,
      Figure imgb0008
       -CONHSO2R21 or -CONHCOOR22;
    • R2 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy; and
    • R3 is H or C1-C6 alkyl;
    • and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • In a sixth aspect, the invention provides a compound of Formula (I) within the scope of any of the first to fifth aspects set out above wherein:
    • R1 is COOH, optionally substituted heterocyclyl, -NHSO2CH3,
      Figure imgb0009
       or -CONHSO2R21 ;
    • where R21 is C1-C6 alkyl, C3-C8 cycloalkyl or CF3;
    • R2 is H, CH3, C2H5, CH3O CF3O F, or Cl; and
    • R3 is H, CH3, or C2H5;
    • and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  • In another aspect, the invention provides a compound of Formula (I) within the scope of any of the first to sixth aspects set out above wherein:
    • R1 and R8 are independently optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted di-deutero-C1-C6-alkyl, optionally substituted C1-C6-alkylphenyl-C1-C6-alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy-C1-C6-alkyl, optionally substituted 5- to 6-membered monocyclic heteroaryl, optionally substituted 7- to 10-membered bicyclic heteroaryl, optionally substituted aryl C1-C6 alkyl, phenylsulfonyl, optionally substituted C2-C6 alkenyl, or 5- to 6-membered monocyclic heteroaryl-C1-C6-alkyl,
    • or R7 and R8 are taken together with the nitrogen to which they are attached to form
      1. (a) a 7- to 10-membered bicyclic heterocyclic ring which is optionally substituted with a phenyl-C1-C6-alkyl group, or
      2. (b) a 5- to 7-membered monocyclic heterocyclic ring which is optionally substituted with 1 or 2 C1-C6 alkyl groups, phenyl, a C1-C6-alkyl-substituted 5- to 7-membered monocyclic heteroaryl, and/or 1 or 2 halo groups; or
      3. (c) a 5- to 7-membered monocyclic heteroaryl which is optionally substituted with a C1-C6 alkyl;
    • R9 is optionally substituted aryl; optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkoxyaryl, optionally substituted C3-C8 cycloalkyl C1-C6 alkyl, optionally substituted 5- to 7-membered monocyclic heterocyclo, optionally substituted 7- to 10-membered bicyclic heterocyclo, optionally substituted 5- to 6-membered monocyclic heteroaryl, optionally substituted 8- to 10-membered bicyclic heteroaryl, optionally substituted C1-C6 alkanoyloxy 5- to 7-membered monocyclic heteroaryl, optionally substituted aryloxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C5-C8 cycloalkenyl, C2-C6 alkynylaryl, C2-C6 alkynyloxyaryl, 5- to 6-membered heteroarylaryl, 5- or 6-membered heterocycloaryl, C3-C8 cycloalkylaryl or C1-C6 alkanoyl.
    • and/or a pharmaceutically acceptable salt thereof, tautomer thereof or stereoisomer thereof.
  • In another aspect, the invention provides a compound of Formula (II)
    Figure imgb0010
     wherein:
    • Y is CR6 or N;
    • Figure imgb0011
      is phenyl substituted with R1 and optionally substituted with R2 and/or R3 or
      Figure imgb0012
      is a 5- to 7-membered monocyclic heteroaryl substituted with R1, and optionally substituted with R2 and/or R3;
    • R1 is COOH, optional substituted tetrazol-5-yl, -NHSO2R20,
      Figure imgb0013
       or -CONHSO2R21;
    • R20 is C1-C6 alkyl or CF3;
    • R21 is C1-C6 alkyl, C3-C8 cycloalkyl or CF3;
    • R2 is H,C1-C6 alkyl, halo, optionally substituted C1-C6-alkoxy or N(C1-C6 alkyl)2,
    • R3 is H, C1-C6 alkyl, C1-C6 alkoxy, or halo;
    • R4 is H, halo or C1-C6 alkyl;
    • R5 is H, halo or C1-C6 alkyl;
    • R6 is H or halo;
    • R7 and R8 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted C3-C8 cycloalkyl, phenylsulfonyl, dideutero-C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl, optionally substituted aryl-C1-C6-alkyl, optionally substituted C2-C6 alkynyl, optionally substituted 5- to 7-membered monocyclic heterocyclo, optionally substituted 7- to 10-membered bicyclic heterocyclo, optionally substituted C1-C6-alkoxy-C1-C6-alkyl, 5- to 7-membered monocyclic heteroaryl-C1-C6-alkyl, C2-C6 alkenyl, or C5-C8 cycloalkenyl,
    • provided that only one of R7 and R8 is H,
    • and wherein the optional substituents on R7 and R8, where possible, are 1 or 2 groups independently selected from hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halo, optionally substituted aryl, optionally substituted C3-C8 cycloalkyl, 5- to 7-membered monocyclic heteroaryl or 5- to 7-membered monocyclic heterocyclic;
    • or R7 and R8 are taken together with the nitrogen to which they are attached to form an optionally substituted 5- to 7-membered monocyclic heterocyclo ring, an optionally substituted 7- to 10-membered bicyclic heterocyclo ring, an optionally substituted 5- to 7-membered monocyclic heteroaryl ring, an optionally substituted 5- to 7-membered monocyclic heteroaryl-substituted 5- to 7-membered monocyclic heterocyclo ring, or a C3-C8-cycloalkyl-C1-C6-alkyl-substituted 7- to 10-membered bicyclic heterocyclo ring;
    • R9 is H, C1-C10 alkyl, aryl, optionally substituted phenyl, C1-C6 alkylphenyl, optinally substituted C1-C6 alkoxyphenyl, di-C1-C6-alkylphenyl, dihalo(C1-C6-alkyl)phenyl, C2-C6 alkynylphenyl, optionally substituted 5- to 7-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heteroaryl, C3-C8 cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C2-C6 alkynyloxyphenyl, C2-C6-alkynyl-C1-C6-alkoxyphenyl, 5- to 7-membered monocyclic heteroarylphenyl, di-C1-C6-alkylaminophenyl, C1-C6 alkylsulfonylaminophenyl, 5- to 7-membered monocyclic heterocyclophenyl, C3-C8 cycloalkyl optionally substituted phenyl, optionally substituted phenyl-C1-C6-alkylcarbonyl, phenyl-C1-C6-alkyl or C1-C6 alkylcarbonyl;
    • and/or a pharmaceutically acceptable salt thereof, a tautomer thereof or stereoisomer thereof.
  • In a further aspect, the invention provides a compound of Formula (II) within the scope of the eighth aspect wherein:
    • Y is CR6;
    • R4 and R5 are independently H or F;
    • R6 is H, F, or Cl;
    • Figure imgb0014
      is phenyl;
    • R1 is COOH,
      Figure imgb0015
      Figure imgb0016
       CN, or
      Figure imgb0017
    • R2 is H, CH3, CH3O, CF3O, C2H5, Cl, or F;
    • R3 is H or F;
    • R7 and R8 are independently H, CH3, C2H5, C3H7, n-C4H9, i-C3H7, i-C4H9, t-C4H9,
      Figure imgb0018
      Figure imgb0019
      Figure imgb0020
      Figure imgb0021
      Figure imgb0022
      Figure imgb0023
      Figure imgb0024
      Figure imgb0025
      Figure imgb0026
    • or R7 and R8 are taken together with the nitrogen to which they are attached to form
      Figure imgb0027
      Figure imgb0028
      Figure imgb0029
      Figure imgb0030
    • R9 is
      Figure imgb0031
      Figure imgb0032
      Figure imgb0033
      Figure imgb0034
      Figure imgb0035
       i-C4H9, t-C4H9, n-C4H9,
      Figure imgb0036
      Figure imgb0037
      Figure imgb0038
      Figure imgb0039
      Figure imgb0040
      Figure imgb0041
      Figure imgb0042
      Figure imgb0043
      Figure imgb0044
      Figure imgb0045
      Figure imgb0046
      Figure imgb0047
      Figure imgb0048
      Figure imgb0049
      Figure imgb0050
      Figure imgb0051
      Figure imgb0052
      Figure imgb0053
      Figure imgb0054
    • and/or a pharmaceutically acceptable salt thereof, a tautomer thereof or stereoisomer thereof.
  • In another aspect, the invention provides a compound selected from the exemplified examples within the scope of the previous aspects, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • In another aspect, the invention provides a compound selected from any subset list of compounds within the scope of any of the above aspects.
  • In another embodiment, the compounds of the invention have human IDO IC50 values :::;1500 nM.
  • In another embodiment, the compounds of the invention have human IDO IC50 values ≤ 250 nM.
  • In another embodiment, the compounds of the invention have human IDO IC50 values ≤ 50 nM.
  • In another embodiment, the compounds of the invention have human IDO IC50 values ≤ 20 nM.
  • In another embodiment, the compounds of the invention have human IDO IC50 values ≤ 10 nM.
    • II. OTHER EMBODIMENTS OF THE INVENTION
  • In another embodiment, the present invention provides a composition comprising one or more compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof
  • In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • In another embodiment, the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • In another embodiment, the present invention provides a process for making a compound of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • In another embodiment, the present invention provides an intermediate for making a compound of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or a solvate thereof.
  • In another embodiment, the present invention provides one or more compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof for use in a method for the treatment and/or prophylaxis of various types of cancer, viral infections and/or autoimmune diseases, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of one or more compounds of the present invention and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent, such as a chemotherapeutic agent or a signal transductor inhibitor.
  • In another embodiment, the present invention provides a compound of the present invention, and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, for use in therapy.
  • In another embodiment, the present invention provides a combined preparation of a compound of the present invention, and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.
  • In another embodiment, the present invention provides a combined preparation of a compound of the present invention, and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof, and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prophylaxis of multiple diseases or disorders associated with the enzymatic activity of IDO.
  • In another aspect, the invention provides a compound described herein and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof for use in a method of treating a patient suffering from or susceptible to a medical condition that is sensitive to enzymatic activity of IDO. A number of medical conditions can be treated. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a compound described herein and/or a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a tautomer thereof. For example, the compounds described herein may be used to treat or prevent viral infections, proliferative diseases (e.g., cancer), and autoimmune diseases.
    • III. THERAPEUTIC APPLICATIONS
  • The compounds and pharmaceutical compositions of the present invention are useful in treating or preventing any disease or conditions that are sensitive to enzymatic activity of IDO. These include viral and other infections (e.g., skin infections, GI infection, urinary tract infections, genito-urinary infections, systemic infections), proliferative diseases (e.g., cancer), and autoimmune diseases (e.g., rheumatoid arthritis, lupus). The compounds and pharmaceutical compositions maybe administered to animals, preferably mammals (e.g., domesticated animals, cats, dogs, mice, rats), and more preferably humans. Any method of administration may be used to deliver the compound or pharmaceutical composition to the patient. In certain embodiments, the compound or pharmaceutical composition is administered orally. In other embodiments, the compound or pharmaceutical composition is administered parenterally.
  • Compounds of the invention can modulate activity of the enzyme indoleamine-2,3-dioxygenase (IDO). The term "modulate" is meant to refer to an ability to increase or decrease activity of an enzyme or receptor. Accordingly, compounds of the invention can be used in methods of modulating IDO by contacting the enzyme with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors of IDO. In further embodiments, the compounds of the invention can be used to modulate activity of IDO in cell or in an individual in need of modulation of the enzyme by administering a modulating (e.g., inhibiting) amount of a compound of the invention.
  • Compounds of the invention can inhibit activity of the enzyme indoleamine-2,3-dioxygenase (IDO). For example, the compounds of the invention can be used to inhibit activity of IDO in cell or in an individual in need of modulation of the enzyme by administering an inhibiting amount of a compound of the invention.
  • The present invention further provides methods of inhibiting the degradation of tryptophan in a system containing cells expressing IDO such as a tissue, living organism, or cell culture. In some embodiments, the present invention provides a compound of composition provided herein for use in methods of altering (e.g., increasing) extracellular tryptophan levels in a mammal by administering an effective amount of a compound of composition provided herein. Methods of measuring tryptophan levels and tryptophan degradation are routine in the art.
  • The present invention further provides a compound or composition recited herein for use in methods of inhibiting immunosuppression such as IDO-mediated immunosuppression in a patient by administering to the patient an effective amount of a compound or composition recited herein. IDO-mediated immunosuppression has been associated with, for example, cancers, tumor growth, metastasis, viral infection, and viral replication.
  • The present invention further provides a compound of the present invention or a pharmaceutical composition thereof for use in methods of treating diseases associated with activity or expression, including abnormal activity and/or overexpression, of IDO in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. Example diseases can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the IDO enzyme, such as over expression or abnormal activity. An IDO-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating enzyme activity. Examples of IDO-associated diseases include cancer, viral infection such as HIV infection, HCV infection, depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases including asthma, rheumatoid arthritis, multiple sclerosis, allergic inflammation, inflammatory bowel disease, psoriasis and systemic lupus erythematosus.
  • As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.
  • As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the IDO enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having IDO, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the IDO enzyme.
  • The term "IDO inhibitor" refers to an agent capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) and thereby reversing IDO-mediated immunosuppression. The IDO inhibitor may inhibit IDO1 and/or IDO2 (INDOL1). An IDO inhibitor may be a reversible or irreversible IDO inhibitor. "A reversible IDO inhibitor" is a compound that reversibly inhibits IDO enzyme activity either at the catalytic site or at a non-catalytic site and "an irreversible IDO inhibitor" is a compound that irreversibly destroys IDO enzyme activity by forming a covalent bond with the enzyme.
  • Types of cancers that may be treated with the compounds of this invention include, but are not limited to, brain cancers, skin cancers, bladder cancers, ovarian cancers, breast cancers, gastric cancers, pancreatic cancers, prostate cancers, colon cancers, blood cancers, lung cancers and bone cancers. Examples of such cancer types include neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiar adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, kidney parenchymal carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma.
  • Thus, according to another embodiment, the invention provides a a compound or composition of the present invention for use in a method of treating an autoimmune disease by providing to a patient in need thereof a compound or composition of the present invention. Examples of such autoimmune diseases include, but are not limited to, collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus. Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal dysmotility, telangiectasia), dermatomyositis, vasculitis (Morbus Wegener's) and Sjögren's syndrome, renal diseases such as Goodpasture's syndrome, rapidly-progressing glomerulonephritis and membrano-proliferative glomerulonephritis type II, endocrine diseases such as type-I diabetes, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroidism, pernicious anemia, gonad insufficiency, idiopathic Morbus Addison's, hyperthyreosis, Hashimoto's thyroiditis and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa and erythema multiforme major, liver diseases such as primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis type-1, autoimmune hepatitis type-2, primary sclerosing cholangitis, neuronal diseases such as multiple sclerosis, myasthenia gravis, myasthenic Lambert-Eaton syndrome, acquired neuromyotomy, Guillain-Barre syndrome (Muller-Fischer syndrome), stiff-man syndrome, cerebellar degeneration, ataxia, opsoclonus, sensoric neuropathy and achalasia, blood diseases such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (Morbus Werlhof), infectious diseases with associated autoimmune reactions such as AIDS, malaria and Chagas disease.
  • One or more additional pharmaceutical agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and/or tyrosine kinase inhibitors can be optionally used in combination with the compounds of the present invention for treatment of IDO-associated diseases, disorders or conditions. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.
  • In the treatment of melanoma, suitable agents for use in combination with the compounds of the present invention include: dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOY™. Compounds according to the invention may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in the treatment of melanoma.
  • Compounds of the invention may also be used in combination with vaccine therapy in the treatment of melanoma. Antimelanorna vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells.
  • Melanomas that are confined to the arms or legs may also be treated with a combination of agents including one or more compounds of the invention, using a hyperthermic isolated limb perfusion technique. This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects. Usually the fluid is warmed to 102° to 104° F. Melphalan is the drug most often used in this chemotherapy procedure. This can be given with another agent called tumor necrosis factor (TNF).
  • Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.
  • Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.
  • Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and droloxafine.
  • Also suitable are cytotoxic agents such as epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.
  • Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (HERCEPTIN®), antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-1O or TGF-β).
  • Other anti-cancer agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4.
  • Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer.
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • The pharmaceutical composition of the invention may optionally include at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more vital steps in signaling pathways, in the normal function of cancer cells, thereby leading to apoptosis. Suitable STIs include, but are not limited to: (i) bcr/abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone: C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2/neu receptor inhibitors such as farnesyl transferase inhibitors (FTI) such as, for example, L-744,832 (Kohl et al., Nat. Med., 1 (8):792-797 (1995)); (iv) inhibitors of Akt family kinases or the Akt pathway, such as, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-O1 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (2003)); and (vi) phosphatidyl inositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one IDO inhibitor may be in separate pharmaceutical compositions. In a specific embodiment of the present invention, at least one IDO inhibitor and at least one STI may be administered to the patient concurrently or sequentially. In other words, at least one IDO inhibitor maybe administered first, at least one STI may be administered first, or at least one IDO inhibitor and at least one STI may be administered at the same time. Additionally, when more than one IDO inhibitor and/or STI is used, the compounds may be administered in any order.
  • The present invention further provides a pharmaceutical composition for the treatment of a chronic viral infection in a patient comprising at least one IDO inhibitor, optionally, at least one chemotherapeutic drug, and, optionally, at least one antiviral agent, in a pharmaceutically acceptable carrier. The pharmaceutical compositions may include at least one IDO inhibitor of the instant invention in addition to at least one established (known) IDO inhibitor. In a specific embodiment, at least one of the IDO inhibitors of the pharmaceutical composition is selected from the group consisting of compounds of formulas (I) and (II).
  • Also provided is above pharmaceutical composition for use in a method for treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.
  • In a specific embodiment of the present invention, at least one IDO inhibitor and at least one chemotherapeutic agent may be administered to the patient concurrently or sequentially. In other words, at least one IDO inhibitor may be administered first, at least one chemotherapeutic agent may be administered first, or at least one IDO inhibitor and the at least one STI may be administered at the same time. Additionally, when more than one IDO inhibitor and/or chemotherapeutic agent is used, the compounds may be administered in any order. Similarly, any antiviral agent or STI may also be administered at any point in comparison to the administration of an IDO inhibitor.
  • Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, human immunodeficiency virus (HIV). Notably, parasitic infections (e.g., malaria) may also be treated by the above methods wherein compounds known to treat the parasitic conditions are optionally added in place of the antiviral agents.
  • In yet another embodiment, the pharmaceutical compositions comprising at least one IDO inhibitor of the instant invention may be administered to a patient to prevent arterial restenosis, such as after balloon endoscopy or stent placement. In a particular embodiment, the pharmaceutical composition further comprises at least one taxane (e.g., paclitaxel (Taxol); see e.g., Scheller et al., Circulation, 110:810-814 (2004)).
  • Suitable antiviral agents contemplated for use in combination with the compounds of the present invention can comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral drugs.
  • Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4C and named beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of IDO-associated diseases or disorders, obesity, diabetes and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
    • PHARMACEUTICAL COMPOSITIONS AND DOSING
  • The invention also provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the compounds of Formula I, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally, one or more additional therapeutic agents described above.
  • The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • The term "pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V. Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.
  • The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.
  • Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
  • A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.
  • The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an anticancer agent or other pharmaceutically active material.
  • Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
  • If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain aspects of the invention, dosing is one administration per day.
  • While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
    • DEFINITIONS
  • Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, "a" and "an" may refer to either one, or one or more.
  • Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
  • When a substituent is noted as "optionally substituted", the substituents are selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, e.g. -SO2NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. -CONH2, substituted carbamyl e.g. -CONHalkyl, - CONHaryl, -CONHarylalkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or arylalkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like, and substituted heterocyclyl, unless otherwise defined.
  • For purposes of clarity and in accordance with standard convention in the art, the symbol
    Figure imgb0055
     is used in formulas and tables to show the bond that is the point of attachment of the moiety or substituent to the core/nucleus of the structure.
  • Additonally, for purposes of clarity, where a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.
  • Additionally, for purposes of clarity, when there is no substituent shown at the end of a solid line, this indicates that there is a methyl (CH3) group connected to the bond.
  • As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 alkyl" denotes alkyl having 1 to 6 carbon atoms. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).
  • The term "alkenyl" denotes a straight- or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. For example, "C2-C8 alkenyl" contains from two to eight carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
  • The term "alkynyl" denotes a straight- or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, "C2-C8 alkenyl" contains from two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. "C1-6 alkoxy" (or alkyloxy), is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-.
  • The term "aryl", either alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to 15 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In certain embodiments of the invention, "aryl" refers to an aromatic ring system which includes, but not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and terahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl and the like. The fused aryls may be connected to another group either at a suitable position on the cycloalkyl ring or the aromatic ring. For example:
    Figure imgb0056
    Figure imgb0057
  • Arrowed lines drawn from the ring system indicate that the bond may be attached to any of the suitable ring atoms.
  • The term "cycloalkyl" refers to cyclized alkyl groups. C3-6 cycloalkyl is intended to include C3, C4, C5, and C6 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". The term "cycloalkenyl" refers to cyclized alkenyl groups. C4-6 cycloalkenyl is intended to include C4, C5, and C6 cycloalkenyl groups. Example cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • The term "cycloalkylalkyl"refers to a cycloalkyl or substituted cycloalkyl bonded to an alkyl group connected to the carbazole core of the compound.
  • "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
  • "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C1-6 haloalkoxy", is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S-, and pentafluoroethyl-S-.
  • The term "benzyl," as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group.
  • As used herein, the term "heterocycle," "heterocyclyl," or "heterocyclic group" is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting ofN, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl.
  • Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).
  • The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
  • Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.
  • As used herein, the term "aromatic heterocyclic group" or "heteroaryl" is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, wherein p is 0, 1 or 2).
  • Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • The term "heterocyclylalkyl"refers to a heterocyclyl or substituted heterocyclyl bonded to an alkyl group connected to the carbazole core of the compound.
  • The term "counter ion" is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate or a positively charged species such as sodium (Na+), potassium (K+), ammonium (RnNHm+ where n=0-4 and m=0-4) and the like.
  • The term "electron withdrawing group" (EWG) refers to a substituent which polarizes a bond, drawing electron density towards itself and away from other bonded atoms. Examples of EWGs include, but are not limited to, CF3, CF2CF3, CN, halogen, haloalkyl, NO2 sulfone, sulfoxide, ester, sulfonamide, carboxamide, alkoxy, alkoxyether, alkenyl, alkynyl, OH, C(O)alkyl, CO2H, phenyl, heteroaryl, -O-phenyl, and -O-heteroaryl. Preferred examples of EWG include, but are not limited to, CF3, CF2CF3, CN, halogen, SO2(C1-4 alkyl), CONH(C1-4 alkyl), CON(C1-4 alkyl)2, and heteroaryl. More preferred examples of EWG include, but are not limited to, CF3 and CN.
  • As used herein, the term "amine protecting group" means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent. Such amine protecting groups fitting these criteria include those listed in Wuts, P. G. M. and Greene, T.W. Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.
  • As referred to herein, the term "substituted" means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).
  • In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative.
  • When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
  • The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Allen, L. V. Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is hereby incorporated by reference.
  • In addition, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
    1. a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);
    2. b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs," A Textbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991);
    3. c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);
    4. d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);
    5. e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and
    6. f) Rautio, J (Editor). Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011.
  • Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C1-6alkyl, C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6 alkanoyloxy-C1-6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1-6alkoxycarbonyloxy-C1-6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art. Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2nd edition, reproduced, 2006); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, 3rd edition, Academic Press, San Diego, CA (2008).
  • The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • The term "solvate" means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
  • As used herein, the term "patient" refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably refers to humans.
  • As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent, i.e., a compound of the invention, that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. The term also includes within its scope amounts effective to enhance normal physiological function
  • As used herein, the term "treating" includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW4 +, wherein W is C1-4 alkyl, and the like.
  • For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
    • METHODS OF PREPARATION
  • The compounds of the present invention may be prepared by methods such as those illustrated in the following Schemes utilizing chemical transformations known to those skilled in the art. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. These Schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein. Different methods may be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). Further, the representation of the reactions in these Schemes as discrete steps does not preclude their being performed in tandem, either by telescoping multiple steps in the same reaction vessel or by performing multiple steps without purifying or characterizing the intermediate(s). In addition, many of the compounds prepared by the methods below can be further modified using conventional chemistry well known to those skilled in the art. All documents cited herein are incorporated herein by reference in their entirety.
  • References to many of these chemical transformations employed herein can be found in Smith, M.B. et al., March's Advanced Organic Chemistry Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, New York (2001), or other standard texts on the topic of synthetic organic chemistry. Certain transformations may require that reactive functional groups be masked by protecting group(s). A convenient reference which provides conditions for introduction, removal, and relative susceptibility to reaction conditions of these groups is Greene, T.W. et al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York (1999).
  • Referring to Scheme 1 set out below, treatment of compounds (i) where X is a halogen, such as Cl, Br or I, and Q is a halogen with amines HNR7R8 and a suitable base in a solvent such as THF, DMF, NMP, dioxane or the like affords intermediates (ii). Generally heating is required. Suitable bases include, but are not limited to aliphatic tertiary amines, sodium or potassium carbonate, or an excess of the reacting primary or secondary amine HNR7R8. Reduction of the nitro group in compounds (ii) to afford anilines (iii) can be effected by various means including catalytic hydrogenation and dissolving metal reductions both in their various forms. See House, H.O., Modern Synthetic Reactions, Second Edition, W.A. Benjamin, Inc., Menlo Park, California, publ. (1972). A preferred method for effecting this reduction without removal of the halogen substituent X involves stirring a solution of (ii) in a wet alcoholic solvent with an acid such as ammonium chloride and finely divided zinc. Treatment of anilines (iii) with an isocyanate R9N=C=O (iva), affords urea compounds (iv). Typically, this reaction is performed in a solvent such as THF at a temperature between ambient and the boiling point of the solvent. Coupling of (iv) with arylboronic acids or esters (ivb), preferably under the conditions of Suzuki (see Kotha, S. et al., Tetrahedron, 58:9633-9695 (2002)) affords compounds of the invention I. Typically, this reaction is performed by heating the halide and the boronic acid or ester to from about 90 to about 98 °C with a base such as aqueous tribasic sodium or potassium phosphate or sodium or potassium carbonate in a solvent such as dioxane, DMF, THF, or NMP using a catalyst such as tetrakis(triphenylphosphine)palladium or Cl2Pd(dppf). Many variations on this reaction involving the use of different temperatures, solvents, bases, anhydrous conditions, catalysts, boronate derivatives, and halide surrogates such as triflates are known to those skilled in the art of organic/medicinal chemistry. Mild conditions have been reported for the coupling of sensitive boronic acid derivatives. See Kinzel, T. et al., J. Am. Chem. Soc., 132(40):14073-14075 (2010). Related coupling reactions for the conversion of (iv) and other aryl halide intermediates described in later Schemes into compounds of the invention include the Heck (olefin) (J. Am. Chem. Soc., 96(4): 1133-1136 (1974)), Stille (organostannane) (Synthesis, 803-815 (1992)), Sonogashira (acetylene) (Sonogashira, K. et al., Tetrahedron Lett., 16(50):4467-4470 (1975)), and Negishi (organozinc) (Aldrichimica Acta, 38(3):71-78 (2005)) coupling reactions.
    Figure imgb0058
  • Scheme 2 describes a preparation of compounds of the invention I similar to that of Scheme 1 but with the transformations performed in a different order. In this Scheme the Suzuki or related coupling is performed on intermediate (iii) to afford aniline (v) which is derivatized by reaction with an isocyanate (iva) to afford compounds of the invention I.
    Figure imgb0059
  • Scheme 3 illustrates a route to compounds of the invention I in which the Suzuki or related coupling is performed on intermediates (ii) to afford intermediates (vi). Reduction under the conditions described above provides anilines (v) which react with isocyanates to afford compounds of the invention I.
    Figure imgb0060
  • Scheme 4 illustrates a method suitable for preparation of compounds of the invention I for which the boronic acid/ester or related derivatives of the
    Figure imgb0061
     group do not readily undergo coupling reactions or are not commercially available or readily accessible. Derivative (iii) can be coupled with boronate ester dimers such as bis(neopentylglycolato)diboron (vii) by heating in a solvent such as DMSO, dioxane, toluene or DMF in the presence of a base such as potassium acetate and a catalyst such as Cl2Pd(dppf) to give aryl boronate esters (viii). These esters can undergo Suzuki or related couplings as described above, to afford intermediates (v). Functionalization of (v) as above by treatment with R9N=C=O (iva) affords compounds of the invention I.
    Figure imgb0062
  • In Scheme 5 the order of synthetic steps is changed from that shown in Scheme 4. Accordingly, aryl boronate esters (viii) are functionalized by coupling with R9N=C=O to give amides or ureas-ureas (x). Alternatively, (x) may be prepared by the conditions shown in Scheme 4 on (iii). These derivatives undergo Suzuki or related coupling reactions to afford compounds of the invention I.
    Figure imgb0063
  • Scheme 6 describes an additional method for the preparation of compounds of the invention I. Treatment of acid or ester (xi) with primary or secondary amines HNR7R8, either in excess or in the presence of a suitable base such as an aliphatic tertiary amine, optionally in the presence of a solvent such as DMF or NMP, at elevated temperature provides adducts (xii). Esters (xii) may be saponified to the corresponding carboxylic acids (xiii) under various conditions familiar to those of ordinary skill in the art. Generally this is effected using an alkali metal hydroxide (MOH) in aqueous solution, preferably with an organic co-solvent such as methanol or THF. Carboxylic acids (xiii) can be converted (by treatment with DPPA and a tertiary amine base) to acyl azides which rearrange (Curtius rearrangement) upon heating to form isocyanates which can be trapped by alcohols R'OH to furnish carbamates (xiv). Many variations on the Curtius rearrangement are familiar to those skilled in the art of organic/medicinal chemistry which have utility for the transformation of carboxylic acids such as (xiii) into carbamates (xiv) or the related amines (iii). Transformation of carbamates (xiv) into the corresponding anilines (xii) is effected in a manner which depends upon the nature of the R' group. Typically, acidic conditions (∼4M HCl in dioxane or∼1:1 TFA-CH2Cl2) are used for acid-labile carbamates (R' = t-Bu). Benzylic carbamates are generally cleaved to the corresponding anilines by exposure to hydrogen gas in the presence of a noble metal catalyst such as Pd or Pt or by phase transfer hydrogenolysis. (Synthesis, 685 (1976).) Methods for transformation of anilines (iii) into compounds of the invention I are described in the other Schemes.
    Figure imgb0064
  • Scheme 7 describes a preparation of compounds of the invention I similar to that of Scheme 6 in which the intermediate isocyanate formed in the Curtius rearrangement is intercepted by an amine R9NH2 to generate urea intermediate (iv). Intermediate (xv) is further transformed using the Suzuki or related coupling into compounds of the invention I.
    Figure imgb0065
  • In Scheme 8 an earlier aniline intermediate (iii) is converted into the corresponding urea derivative (iv) as shown. Suzuki or related coupling reactions serve to transform this intermediate into compounds of the invention I.
    Figure imgb0066
  • Scheme 9 describes a preparation of compounds of the invention starting from dibromoaniline or related dihaloheterocycles (xx) where X and Q are each halo. Introduction of the NHCONHR9 group is accomplished as in the above Schemes to provide dibromourea (xxi). This intermediate can undergo Suzuki or related coupling at the less hindered bromide to afford intermediate (xxii). Finally, treatment with amines HNR7R8 and an appropriate catalyst, preferably using the conditions of Buchwald affords compounds of the invention I.
    Figure imgb0067
  • Intermediates prepared in the above Schemes may require further elaboration in order to be converted into compounds of the invention. Examples of this are provided in the following Schemes.
  • Scheme 10 illustrates the conversion of nitriles (xxiii) into tetrazole intermediates (xxiv) which can be converted to compounds of the invention as described herein. Typically, the nitrile (xxiii) is prepared by chemistry described above (often Suzuki coupling on an intermediate such as (iii)) and heated with an azide such as tributyltinazide in a solvent such as toluene at or near the boiling point. Compounds (xxiv) may be converted to compounds of the invention I or may be intermediates which are transformed into compounds of the invention I by methods taught in the previous schemes. This methodology could be used to prepare heteroaromatic tetrazole derivatives in addition to the phenyl derivatives shown.
    Figure imgb0068
  • Scheme 11 illustrates the transformation of intermediates or compounds of the invention into further intermediates or compounds of the invention by functional group interconversions. Accordingly, alkyl ethers (xxix) can be converted to phenols by treatment with Lewis acids such as BBr3, preferably in a solvent such as CH2Cl2 or CH2ClCH2Cl. Re-alkylation affords new ether derivatives (xxx) in which the carboxylic acid has also been alkylated. Alternatively, phenols may be alkylated using the Mitsunobu reaction. (Reviewed in: Kumara Swamy, K.C. et al., "Mitsunobu and Related Reactions: Advances and Applications", Chem. Rev., 109:2551-2651 (2009).) Further transformation affords carboxylic acids derivatives (xxxi) or protected intermediates which could be further transformed into compounds of the invention I. The saponification reaction is generally accomplished by the use of an alkali metal hydroxide in aqueous or mixed aqueous/organic solvents. This methodology could be used to prepare heteroaromatic carboxylate derivatives in addition to the phenyl derivatives shown.
    Figure imgb0069
  • The carboxylic acids prepared in Scheme 11 can be derivatized (Scheme 12) to provide acylsulfonamides (xxxii) which may be transformed into compounds of the invention I using chemistry described in the schemes above. Generally, the conversion of carboxylic acids to acylsulfonamides is accomplished using a coupling reagent such as CDI and a base such as DBU in a solvent such as DMF or THF. This methodology could be used to prepare heteroaromatic acylsulfonamide derivatives in addition to the phenyl derivatives shown.
    Figure imgb0070
  • The methods described in the Schemes above can be used to prepare amine derivatives (xxxiii) which may be further elaborated by treatment with a base and an electrophile such as an acyl or sulfonyl chloride or a carboxylic or sulfonic acid anhydride or activated esters or the like to prepare carboxamide or sulfonamide compounds of the invention I (Scheme 13). Alternatively, this derivatization may be performed on an earlier intermediate which may be transformed into compounds of the invention I using reactions described in the Schemes above. This methodology may be used to prepare heteroaromatic amine derivatives in addition to the aniline derivatives shown.
    Figure imgb0071
    • General Experimental
  • Air- or moisture-sensitive reactions were generally performed under an atmosphere of nitrogen or argon in anhydrous solvents (EMD DRISOLV®). Zinc (-325 mesh) for nitro group reduction was obtained from Alfa Aesar. Reaction concentrations indicated in the tables and procedures are given in units of molar and are approximate. Temperatures are given in degrees Celsius. Reactions were monitored for completeness by thin layer chromatography (TLC) or tandem liquid chromatography-mass spectroscopy (LCMS). For TLC, 0.25 mm plates coated with Silica60/F254 were used with visualization by UV light at ∼254 nM, exposure to iodine vapor, or heating with PMA (phosphomolybdic acid solution), ninhydrin in ethanol, anisaldehyde solution, or ceric ammonium molybdate solution.
  • Unless otherwise specified, "dried" refers to the addition of anhydrous MgSO4 followed by filtration and rinsing the residual solids with an appropriate organic solvent. "Stripped" means concentration under reduced pressure, generally on a rotary evaporator. "Silica gel chromatography", "flash chromatography", or "chromatographed on silica gel" refers to glass column chromatography performed in a manner similar to that described by Still (J. Org. Chem., 43:2923 (1978)). Typically silica gel 60 (EMD, 230-400 mesh ASTM) is used with solvents from JT Baker or Mallinckrodt. HPLC refers to purification by reverse-phase high-performance liquid chromatography generally on C18 columns using the stated mobile phases. Analytical HPLC runs were performed using the columns, flow rates, and mobile phases indicated. It is understood that analytical HPLC retention times (Tr) are reported in minutes, and may be dependent on temperature, pH, and other factors. ISCO refers to chromatography on pre-packed silica gel cartridges using automated systems marketed by Teledyne Isco. For all chromatographic purifications the isolation of product by concentration of the appropriate fractions by evaporation at or below ambient pressure is implied. Melting points were determined on a Thomas-Hoover Uni-Melt apparatus and are uncorrected. Generally, mass spectral results are reported as the (M+H)+ value. For halogenated compounds where two or more peaks are significant, m/z for one peak in the cluster, generally the most intense, is reported. 1H NMR spectra were recorded on dilute solutions at 400 or 500 MHz on VARIAN® or JEOL® instruments in the solvents indicated. Chemical shifts are reported in parts per million (ppm) downfield from internal tetramethylsilane (TMS) or from the position of TMS inferred by the deuterated NMR solvent. Apparent multiplicities are reported as: singlet-s, doublet-d, triplet-t, quartet-q, or multiplet-m. Peaks which exhibit broadening are further denoted as br. Integrations are approximate. It should be noted that integration intensities, peak shapes, chemical shifts and coupling constants can be dependent on solvent, concentration, temperature, pH, and other factors. Further, peaks which overlap with or exchange with water or solvent peaks in the NMR spectrum may not provide reliable integration intensities.
  • Unless otherwise specified, the various substituents of the compounds as employed herein are defined in the same manner as compounds of the invention of Formula (I).
  • For ease of reference, the following abbreviations are used herein. Abbreviations
    AcOH, HOAc acetic acid
    ACN acetonitrile
    Ac2O acetic anhydride
    ADDP 1,1'-(azodicarbonyl)dipiperidine
    aq. aqueous
    Bn benzyl
    Boc t-butyl carbamate
    Boc2O di-t-butyl dicarbonate
    BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
    Bu butyl
    Cbz benzyl carbamate
    conc. concentrated
    DCE dichloroethane
    DCM dichloromethane
    DIAD diisopropyl azodicarboxylate
    DIEA N,N-diisopropylethylamine
    DMAP 4-N,N-dimethylaminopyridine
    DMF dimethylformamide
    DMSO dimethylsulfoxide
    DMT-MM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
    EDC 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride
    Et ethyl
    EtOAc ethyl acetate
    EtOH ethanol
    Et2O diethyl ether
    Et3N triethylamine
    Fmoc 9-fluorenylmethyl carbamate
    h hour(s)
    HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
    HOAt 1-hydroxy-7-azabenzotriazole
    HPLC high performance liquid chromatography
    i-PrOH isopropanol
    KOAc potassium acetate
    LAH Lithium aluminum hydride
    min minute(s)
    Me methyl
    MeCN acetonitrile
    MeOH methanol
    Me2NH dimethylamine
    NaHMDS sodium bis(trimethylsilyl)amide
    Na(OAc)3BH sodium triacetoxyborohydride
    n-BuLi n-butyllithium
    NCS N-chlorosuccinimide
    NMM N-methylmorpholine
    NMP n-methylpyrrolidinone
    NMR nuclear magnetic resonance
    OTf trifluoromethylsulfonyloxy
    Pd/C palladium on carbon
    Pd(dppf)2Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
    Pd(OAc)2 palladium acetate
    Pd(PPh3)4 tetrakis(triphenylphosphine)palladium
    Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
    PE Petroleum ether
    Ph phenyl
    PhMe toluene
    Ph2TfN 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl methanesulfonamide
    PPh3 triphenyl phosphine
    RB Round-bottom flask
    rt room temperature
    sat. saturated
    t-Bu tertiary butyl
    t-BuOH tertiary butanol
    TFA trifluoroacetic acid
    Tf2O trifluoromethylsulfonic anhydride
    THF tetrahydrofuran
    TMS trimethylsilyl
    TsO p-toluenesulfonyl
    • Analytical HPLC Conditions:
    1. a Waters Sunfire C18 4.6 x 150mm 3.5 µ. 1 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 15 min.
    2. b Waters Sunfire C18 4.6 x 150mm 3.5 µ. 1 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 10 min.
    3. c YMC S5 ODS, 4.6 x 50 mm. 4 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 12 min.
    4. d Waters X-Bridge Phenyl 4.6 x 150 mm 3.5 µ, 1 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 10 min.
    5. e YMC S5 ODS, 4.6 x 50 mm. 4 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 4 min.
    6. f YMC S5 ODS, 4.6 x 50 mm. 1 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 15 min.
    7. g Sunfire C18 3.0 x 150mm 3.5 µ. 0.5 mL/min, 14-95% acetonitrile-water, 0.05% TFA, gradient over 12 min.
    8. h YMC pro c18 S5 ODS, 4.6 x 50 mm. 4 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 12 min.
    9. i SUPELCO® Ascentis 4.6 x 50 mm, 2.7µ C18, 4mL/min, 5-95% acetonitrile-water, 10 mM NH4OAc, gradient over 4 min. (Column temp. = 35 °C.)
    10. j Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.
    11. k Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.
    12. l Luna C18, 4.6 x 30 mm, 3-µm particles; 10-90% MeOH-water (0.1% TFA in both phases) gradient over 5 min. Flow: 4 mL/min.
    13. m ZORBAX® SB C18, 4.6 x 75 mm, 50-90% MeOH-water (0.1% TFA in both phases) gradient over 8 min. Flow: 2.5 mL/min.
    14. n YMC S5 ODS, 4.6 x 50 mm. 4 mL/min, 10-90% methanol-water 0.05% TFA, gradient over 4 min.
    15. o Luna C18, 4.6 x 30 mm, 3-µm particles; 10-86% CH3CN-water (10 mM NH4OAc in both phases) gradient over 2 min. Flow: 4 mL/min.
    16. p Luna C18, 4.6 x 30 mm, 3-µm particles; 10-85.5% MeOH-water (0.1% TFA in both phases) gradient over 2 min. Flow: 4 mL/min.
    17. q Luna C18, 4.6 x 30 mm, 3-µm particles; 10-90% MeOH-water (0.1% TFA in both phases) gradient over 3.5 min. Flow: 4 mL/min.
    18. r PHENOMENEX®, 2.0 x 30 mm, 2.5-µm particles; 26-90% MeOH-water (0.1% TFA in both phases) gradient over 3 min. Flow: 1 mL/min.
    19. s Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.
    20. t Column: Xbridge (150 x 4.6 mm), 3.5 µ; Method: 0.05% TFA in water pH2.5; Mobile Phase A: Buffer: acetonitrile (95:5) Mobile Phase B: acetonitrile: Buffer (95:5) Flow: 1.0 ml/min.
    21. u Column: Sunfire (150 x 4.6 mm), Method: 0.05% TFA in water pH2.5 Mobile Phase A: Buffer: acetonitrile (95:5) Mobile Phase B: acetonitrile: Buffer (95:5) Flow: 1.0 ml/min.
    22. v Column: Ascentis Express C8 (5 x 2.1 mm) 2.7 µM particles, 10 mM in ammonium formate. 98:2 to 2:98 water-acetonitrile gradient over 1.5 min. Flow: 1.0 ml/min.
    23. w Phenomenex-Luna C18 3 um 4.6 x 30mm, 0%B-95%B with flow rate 4 mL/min and 2 min gradient time; Solvent A: 10% water/90% acetonitrile with 10 mM NH4OAc; Solvent B: 10% water/90% acetonitrile with 10 mM NH4OAc, wavelength 220 nM.
    24. x Phenomenex Luna C18, 2.0 x 30 mm, 5-µm particles; Mobile Phase A: 10:90 water:MeOH 0.1% TFA; Mobile Phase B: 10:90 water:MeOH 0.1%TFA; Temperature: RT; Gradient: 0% B for a 0.2min hold, then 0-100%B over 2.5 minutes, then a 3-minute hold at 100% B; Flow: 1.5 mL/min.
    25. y Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-µm particles; Mobile Phase A: water with 0.05% TFA; Mobile Phase B: acetonitrile with 0.05% TFA; Temperature: 50°C; Gradient: 2-98% B over 1 minutes, then a 0.5-minute hold at 100% B; Flow: 0.8 mL/min.
    Example 1 1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0072
    • 1A. 4-Bromo-N,N-diisobutyl-2-nitroaniline
  • Figure imgb0073
  • A solution of diisobutylamine (0.284 g, 2.200 mmol) and 4-bromo-1-fluoro-2-nitrobenzene (0.220 g, 1 mmol) was heated at 130 °C for 6h. The reaction was cooled and diluted with ethyl acetate. This solution was washed with aq. HCl then brine, dried, and stripped to afford 0.3g (87%) of 4-bromo-N,N-diisobutyl-2-nitroaniline (1A) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90(d, 1 H, J = 2.6 Hz); 7.60(dd, 1 H, J = 9.0, 2.4 Hz); 7.32(d, 1 H, J = 9.0 Hz); 2.89(d, 4H, J = 7.3 Hz); 1.76-1.86(m, 2H); 0.77(d, 12H, J = 6.4 Hz). MS(ES): m/z = 331 [M+H]+.
    • 1B. 4-Bromo-N1,N1-diisobutylbenzene-1,2-diamine
  • Figure imgb0074
  • To a stirred solution of 4-bromo-N,N-diisobutyl-2-nitroaniline (1A) (0.9 g, 2.7 mmol) in ethanol (Volume: 10 mL) was added 2 mL of water followed by ammonium chloride (1.46 g, 27.3 mmol) then zinc (1.79 g, 27.3 mmol). The mixture was stirred 1h, cooling to RT then diluted with dichloromethane and filtered. The filtrate was washed with water, dried, and stripped to afford an oil. Chromatography on silica gel (gradient elution with ether-hexanes) afforded, after removal of solvent, 0.66g (77%) of 4-bromo-N1,N1-diisobutylbenzene-1,2-diamine (1B) as a pale purple oil. MS(ES): m/z = 301 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.92(d, 1 H, J = 8.4 Hz); 6.81(d, 1 H, J = 2.2 Hz); 6.63(dd, 1 H, J = 8.1, 2.2 Hz); 2.53(d, 4H, J = 7.0 Hz); 1.59-1.69(m, 2H); 0.84(d, 12H, J = 6.6 Hz).
    • 1C. 1-(5-Bromo-2-(diisobutylamino)phenyl)-3-p-tolylurea
  • Figure imgb0075
  • To a stirred solution of 4-bromo-N1,N1-diisobutylbenzene-1,2-diamine (1B) (0.1 g, 0.33 mmol) in THF (Volume: 1 mL) was added 1-isocyanato-4-methylbenzene (0.067 g, 0.50 mmol). The solution was stirred 1h at 50 °C then purified by silica gel chromatography (gradient elution with EtOAc-hexanes). Concentration of the appropriate fractions afforded 0.12g (79%) of 1-(5-bromo-2-(diisobutylamino)phenyl)-3-p-tolylurea (1C) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (1 H, s), 8.20 (1 H, d, J = 2.4 Hz), 7.95 (1 H, s), 7.35 (2 H, d, J=8.4 Hz), 7.18(d, 1H, J = 8.6 Hz), 7.07-7.13 (3 H, m), 2.68(4H, d, J = 6.6 Hz), 2.24 (3 H, s), 1.58-1.68 (2H, m), 0.82 (12H, d, J = 6.6 Hz). MS(ES): m/z = 434 [M+H]+.
    • 1. 1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0076
  • To a suspension of 2-(1H-tetrazol-5-yl)phenylboronic acid (0.062 g, 0.32 mmol) and 1-(5-bromo-2-(diisobutylamino)phenyl)-3-p-tolylurea (1C) (0.07 g, 0.162 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.019 g, 0.016 mmol) in degassed DMF (Volume: 2 mL) was added aq. potassium carbonate (0.540 mL, 0.809 mmol). The mixture was placed under nitrogen and heated at 100 °C for 2h. The reaction was cooled, diluted with aq. HCl, and extracted twice with dichloromethane. The organic extracts were combined, dried, stripped, and purified by prep. HPLC (Axia 30 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate fraction afforded 0.061g (74%) of 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea (1) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (1 H, s), 7.90 (1 H, d, J=2.2 Hz), 7.83 (1 H, s), 7.65-7.70 (1 H, m), 7.60 (1H, d, J = 7.7 Hz), 7.50-7.57 (2 H, m), 7.33 (2 H, d, J=8.4 Hz), 7.05-7.10 (3 H, m), 6.52 (1 H, dd, J=8.1, 2.1 Hz), 2.66 (4 H, d, J=6.8 Hz), 1.59-1.69 (2H, m), 0.83 (12H, d, J =6.6 Hz). MS(ES): m/z = 498 [M+H]+,
  • Using the method described (Examples 1A and 3A are representative), the appropriate amines HNR7R8 were reacted with 2-fluoro-5-bromonitrobenzene in the indicated (Table 1A) solvents at the indicated temperatures. Any additional tertiary amine base utilized in these transformations is indicated in the table. This afforded nitroanilines which were processed by the procedure for the conversion of 1A into 1B to afford intermediates. Table 1A
    Preparation of Intermediates (iii) from a Commercially-Available Fluoro nitrobenzene
    Figure imgb0077
    NR7R8 Amine eq. Solvent Conc. Base Temp Time (M+H)+ HPLC Tr
    iiia
    Figure imgb0078
         		3 None None 140 20h 319 4.48l
    iiib
    Figure imgb0079
         		2 THF 0.4M None 50 3h 285 2.40l
    iiic
    Figure imgb0080
         		2 THF 0.1M None 50 3h 299 2.20o
    iiid
    Figure imgb0081
         		2 THF 0.4M None 50 3h 311 3.17l
    iiif
    Figure imgb0082
         		2.2 THF 0.8M None 60 1h 269 2.92l
    iiig
    Figure imgb0083
         		1.3 HCl salt DMF 1 M Et3N 2.5eq. 100 2h 269 2.92l
    iiih
    Figure imgb0084
         		3 NMP 1M None 100 0.5h 224 (M+H - 2 MeOH)+ 2.48l
    iiii
    Figure imgb0085
         		3 NMP 1M None 100 0.5h 303 1.68o
    iiij
    Figure imgb0086
         		3 NMP 1M None 60 1.5h 285 2.32l
    iiik
    Figure imgb0087
         		1.5 NMP 2M Et3N 1.4eq. 55 2h 251 2.15l
    iiil
    Figure imgb0088
         		1.2 HCl salt NMP 0.6M Et3N 2.2eq. 130 1.5h 325 3.14l
    iiim
    Figure imgb0089
         		1.1 HCl salt NMP 1M DIEA 2eq. 135 4h 339 4.25l
    iiin
    Figure imgb0090
         		1.2 HCl salt NMP 1M DIEA 2.2eq. 130 2h 297 3.66l
    iiio
    Figure imgb0091
         		3 NMP 1M None 100 17h 275 2.06l
    iiip
    Figure imgb0092
         		1.1 HCl salt NMP 1M Et3N 2.3eq. 100 3h 285 2.59l
    iiiq
    Figure imgb0093
         		1.2 HCl salt NMP 1M DIEA 3eq. 110 3h 299 3.10l
    iiir
    Figure imgb0094
         		1.2 HCl salt NMP 1M DIEA 3eq. 120 3h 325 1.71p
    iiis
    Figure imgb0095
         		1.2 HCl salt NMP 1M DIEA 2.5eq. 120 3h 313 1.72p
    iiit
    Figure imgb0096
         		3 NMP 1M None 100 1h 301 1.79p
    iiiu
    Figure imgb0097
         		1.3 HCl salt NMP 1M DIEA 2.8eq. 120 20 299 1.81p
    iiiv
    Figure imgb0098
         		1 HCl salt NMP 0.5M DIEA 3eq. 135 5h 313 2.05p
    iiiw
    Figure imgb0099
         		1.4 HCl salt NMP 0.5M DIEA 3eq. 110 3h 321 2.43p
    iiix
    Figure imgb0100
         		1.4 HCl salt NMP 0.6M DIEA 3eq. 110 3h 287 2.54p
    iiiy
    Figure imgb0101
         		2.5 NMP 1M None 110 3h 285 2.06p
    iiiz
    Figure imgb0102
         		1.7 NMP 1M DIEA 1.3eq. 140 24h 327 2.88q
    iiiab
    Figure imgb0103
         		1.2 HCl salt NMP 1M DIEA 2.5eq. 125 4h 313 2.61l
    iiiac
    Figure imgb0104
         		1.7 NMP 1M DIEA 1.3eq. 140 24h 329 2.86q
    iiiad
    Figure imgb0105
         		1.7 HCl salt NMP 1M DIEA 3eq. 140 24h 287 2.321
    iiiag
    Figure imgb0106
         		1.4 NMP 1M DIEA 1.3eq. 140 18h 299 2.34q
    iiiah
    Figure imgb0107
         		1.4 NMP 1M DIEA 1.2eq. 140 4h 313 2.64q
    iiiaj
    Figure imgb0108
         		1.4 HCl salt NMP 0.6M DIEA 3eq. 140 18h 327 2.01q
    iiiak
    Figure imgb0109
         		4 NMP 1M None 140 4h 259 1.73q
    iiial
    Figure imgb0110
         		0.8 NMP 1M DIEA 1.4eq. 130 5h 299 2.08q
    iiiam
    Figure imgb0111
         		1.4 NMP 1.5M Et3N 1.1eq. 100 2h 321 3.90q
    iiian
    Figure imgb0112
         		1.4 NMP 1M DIEA 1.2eq. 130 19h 369 2.76q
    iiiao
    Figure imgb0113
         		1 NMP 1M Et3N 1.2eq. 140 6h 395 2.84r
    iiiap
    Figure imgb0114
         		1.4 HCl salt NMP 1M DIEA 1.2eq. 130 19h 371 2.39q
    iiiaq
    Figure imgb0115
         		1.1 HCl salt NMP 1M DIEA 2.4eq. 150 18h 335 2.51q
    iiiar
    Figure imgb0116
         		1.3 NMP 1.3M DIEA 1.5 eq. 130 20h 339 2.63q
    iiias
    Figure imgb0117
         		3 DMF 0.6M None 80 1h 273 4.59l
    iiiat
    Figure imgb0118
         		2 NMP 1.5M DIEA 1.2eq. 110-115 7h 351 1.23k
    iiiau
    Figure imgb0119
         		1.1 NMP 1.5M DIEA 1.1eq. 110-120 6h 369 3.35l
    iiiav
    Figure imgb0120
         		1.1 NMP 1.5M DIEA 1.2eq. 120 4h 397 3.97l
    iiiaw
    Figure imgb0121
         		1.3 NMP 1.5M DIEA 2eq. 140 30 369 2.06p
    iiiax
    Figure imgb0122
         		4 NMP 1.5M None 120 72 313 4.641
    iiiay
    Figure imgb0123
         		2 NMP 1.5M DIEA 1eq. 130 16 327 1.63p
    iiiaz
    Figure imgb0124
         		1.5 NMP 1.5M DIEA 1 eq. 100 1 331 3.40l
    iiibc
    Figure imgb0125
         		10 None None 46 3h (M-H)- 271 2.24v
    iiibd
    Figure imgb0126
         		1.2 DMF 0.5M K2CO3 3eq 80 18h (M-H)- 266 1.84v
  • Using the methods described (Example 1A and 3A are representative), the appropriate amines HNR7R8 were reacted with 2,4-difluoro-5-bromonitrobenzene in the indicated (Table 1B) solvents at the indicated temperatures. Any additional tertiary amine base utilized in these transformations is indicated in the table. This afforded nitroanilines which were processed by the procedure for the conversion of 1A into 1B to afford the intermediates (iii).
  • Certain aniline derivatives iii may be made by alkylation of nitroanilines followed by reduction as described above. The procedure below is illustrative.
    • 4-bromo-N-cyclohexyl-N-(2-methylallyl)-2-nitroaniline
  • Figure imgb0127
  • A solution of 4-bromo-N-cyclohexyl-2-nitroaniline (0.598 g, 1.999 mmol) in DMF (4 mL) was treated with 3-bromo-2-methylprop-1-ene (0.403 mL, 4.00 mmol) followed by sodium hydride (0.137 g, 4.00 mmol). The reaction was stirred at RT for 15 min. and then treated with an additional 0.3 g of sodium hydride and 0.4 mL of alkylating agent. The reaction was stirred an additional 4h at RT then carefully quenched with glacial HOAc then diluted with water. This dark mixture was ext. with ether, and the org. ext. was dried, stripped, and submitted purified by ISCO. Concentration of the appropriate fractions afforded 0.32 g (43%) of 4-bromo-N-cyclohexyl-N-(2-methylallyl)-2-nitroaniline as an oil. LCMS: 353 (M + H)+. HPLC Tr: 2.48p.
    • 4-bromo-N-(4-chlorobenzyl)-N-cyclohexyl-2-nitroaniline
  • Figure imgb0128
  • The title compound was prepared from 4-bromo-N-cyclohexyl-2-nitroaniline and 4-chlorobenzylbromide using the procedure for preparation of 4-bromo-N-cyclohexyl-N-(2-methylallyl)-2-nitroaniline. LCMS: 425 (M + H)+. HPLC Tr: 5.48l.
  • Reduction of the nitro groups as described above affords anilines iii: Table 1B
    Ex. No. NR7R8 (M+H)+ HPLC Tr method
    iiiba
    Figure imgb0129
         		323 1.99p
    iiibb
    Figure imgb0130
         		395 4.69l
    • Preparation of Intermediates from a Commercially-Available Difluoronitrobenzene
  • Figure imgb0131
    Ex. No. NR7R8 Amine eq. Solvent conc. Base Temp Time (M+H)+ HPLC Tr method
    iiica
    Figure imgb0132
         		1.3 THF 0.3M Et3N 1.3eq. 60 1.5h 285 3.43l
    iiicb
    Figure imgb0133
         		1.2 NMP 0.7M DIEA 1.3eq. 140 24h 345 2.39r
    iiicc
    Figure imgb0134
         		1.2 HCl salt NMP 0.5M Et3N 2.2eq. 130 1.5h 325 3.14l
    iiicd
    Figure imgb0135
         		1.1 DMF 1M Et3N 1.5 eq. 60 1.5h 317 2.25p
  • Preparation of Intermediates from a Commercially-Available Difluoronitrobenzene
    Figure imgb0136
  • 4-bromo-N1-cyclohexyl-6-fluoro-N1-isobutylbenzene-1,2-diamine was prepared from 5-bromo-1,2-difluoro-3-nitrobenzene and N-isobutylcyclohexanamine by the procedures outlined in the examples above.
    • Example 2 1-(4-(Cyclohexyl(methyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(4-(trifluoromethyl)phenyl)urea
  • Figure imgb0137
    • 2A. N4-Cyclohexyl-N4-methyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine
  • Figure imgb0138
  • To a suspension of 2-(1H-tetrazol-5-yl)phenyl-boronic acid (0.68 g, 3.6 mmol) and 4-bromo-N1-cyclohexyl-N1-methylbenzene-1,2-diamine (iiib) (0.57 g, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.100 mmol) in DMF (Volume: 8 mL) was added aq. potassium carbonate (5.00 mL, 10.0 mmol). The mixture was placed under nitrogen and heated at 100 °C for 3h. LCMS indicated reaction is ∼50% complete, so it was treated with an additional 0.15 g of boronic acid and 0.04g of catalyst and heated at 90 °C overnight. The reaction was cooled and poured into diluted aq. HOAc. The resulting mixture was extracted twice with chloroform. The combined organic extracts were dried, stripped, and chromatographed on silica gel (gradient elution with EtOAc-hexanes, 1% HOAc) to afford, after removal of solvent, N4-cyclohexyl-N4-methyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (2A) (0.17 g, 23% yield) as a beige foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93(br. s, 1H); 7.48-7.66(m, 4H); 6.79(d, 1 H, J = 7.9 Hz); 6.52(d, 1H, J = 2.2 Hz); 6.12(dd, 1H, J = 7.9, 1.8 Hz); 4.6-4.8(br. s, 2H); 2.68-2.76(m, 1H); 1.90(s, 3H); 1.64-1.76(m, 4H); 1.50-1.58(m, 1H); 1.26-1.39(m, 2H); 1.02-1.19(m, 3H). MS(ES): m/z = 349 [M+H]+,
    • 2. 1-(4-(Cyclohexyl(methyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(4-(trifluoromethyl)phenyl)urea
  • Figure imgb0139
  • To a stirred solution of N4-cyclohexyl-N4-methyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (2A) (0.015 g, 0.043 mmol) in THF (Volume: 0.2 mL) was added 1-isocyanato-4-(trifluoromethyl)benzene (0.014 g, 0.073 mmol). The solution was stirred 2h at 50 °C then cooled and purified by prep. HPLC (Axia 21 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate fraction afforded 1-(4-(cyclohexyl(methyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (2) (0.012 g, 49% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.92(s, 1H); 8.44(s, 1H); 8.02(s, 1H); 7.60-7.71(m, 6H); 7.52-7.56(m, 2H); 7.12(d, 1H, J = 8.1 Hz); 6.58(d, 1H, J = 7.7 Hz); 2.60-2.66(m, 1H); 2.58(s, 3H); 1.81-1.88(m, 2H); 1.66-1.74(m, 2H); 1.50-1.57(m, 1H); 1.01-1.29(m, 5H). MS(ES): m/z = 536 [M+H]+.
    • Example 3 1-(4-(Cyclopentyl(methyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0140
    • 3A. 4-Bromo-N-cyclopentyl-N-methyl-2-nitroaniline
  • Figure imgb0141
  • To a stirred solution of 4-bromo-1-fluoro-2-nitrobenzene (0.440 g, 2 mmol) in THF (Volume: 2 mL) was added N-methylcyclopentanamine (0.595 g, 6.00 mmol). The solution was stirred 1h at 60 °C then cooled and stirred at RT. The solution was diluted with ether and washed with dilute aq. HOAc then aq. sodium bicarbonate then brine. The organic phase was dried and stripped to afford 4-bromo-N-cyclopentyl-N-methyl-2-nitroaniline (3A) (0.57 g, 91% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94(d, 1H, J = 2.4 Hz); 7.64(dd, 1H, J = 9.0, 2.4 Hz); 7.30(d, J = 9.0 Hz); 3.70-3.79(m, 1H); 2.58(s, 3H); 1.44-1.83(m, 10H). MS(ES): m/z = 301 [M+H]+.
    • 3B. N-Cyclopentyl-N-methyl-3-nitro-2'-(1H-tetrazol-5-yl)biphenyl-4-amine
  • Figure imgb0142
  • A suspension of 2-(1H-tetrazol-5-yl)phenylboronic acid (0.190 g, 1.000 mmol) and 4-bromo-N-cyclopentyl-N-methyl-2-nitroaniline (3A) (0.150 g, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol) in degassed DMF (Volume: 4 mL) was treated with aq. potassium carbonate (1.667 mL, 2.500 mmol). The mixture was placed under nitrogen and heated at 95 °C for 2.5h. The reaction was diluted with ∼4 mL of water and filtered hot. The filtrate was diluted to 40 mL with water, brought to pH3 with conc. HCl, and stirred vigorously to induce precipitation of product. The resulting red solid was filtered, rinsed with water, and air-dried to afford N-cyclopentyl-N-methyl-3-nitro-2'-(1H-tetrazol-5-yl)biphenyl-4-amine (3B) (0.175 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65-7.69(m, 2H); 7.55-7.62(m, 2H); 7.53(d, 1H, J = 2.2 Hz); 7.20(d, 1H, J = 8.6 Hz); 7.09(dd, 1H, J = 8.6, 2.2 Hz); 3.77-3.86(m, 1H); 2.58(s, 3H); 1.76-1.89(m, 2H); 1.46-1.69(m, 8H). MS(ES): m/z = 365 [M+H]+.
    • 3C. N4-Cyclopentyl-N4-methyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine
  • Figure imgb0143
  • A suspension of N-cyclopentyl-N-methyl-3-nitro-2'-(1H-tetrazol-5-yl)biphenyl-4-amine (0.16 g, 0.439 mmol) and palladium on carbon (0.05 g, 0.047 mmol) in ethanol (Volume: 5 mL) was treated with HCl in dioxane (0.132 mL, 0.527 mmol) and hydrogenated at 45 psi for 30 min. Catalyst was removed by filtration, and the organic solution was stripped and purified by prep. HPLC (Axia 30 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate fractions afforded N4-cyclopentyl-N4-methyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (3C) (0.05 g, 34% yield) as a glass. HPLC Tr: 2.761. MS(ES): m/z = 335 [M+H]+.
    • 3. 1-(4-(Cyclopentyl(methyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0144
  • To a solution of N4-cyclopentyl-N4-methyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (0.02 g, 0.060 mmol) in THF (Volume: 0.5 mL) was added 1-isocyanato-4-methylbenzene (0.012 g, 0.090 mmol). The solution was stirred 2h at 50 °C then purified by prep. HPLC (Axia 21 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate fraction afforded 1-(4-(cyclopentyl(methyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea (3) (0.009 g, 30.6% yield) as a white powder. MS(ES): m/z = 468 [M+H]+. HPLC Tr: 12.28d.
    • Example 4 N-(4'-(Diisobutylamino)-3'-(3-p-tolylureido)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide
  • Figure imgb0145
    • 4A. N-(2-Bromophenyl)-1,1,1-trifluoromethanesulfonamide
  • Figure imgb0146
  • 2-Bromoaniline (300 mg, 1.744 mmol) was taken up in DCM (Volume: 5 mL) and cooled to 0 °C. Pyridine (2.82 mL, 34.9 mmol) was added, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.440 mL, 2.62 mmol). The reaction was stirred at 0 °C and slowly warmed to rt overnight. The reaction was diluted with DCM, washed with 1N HCl, then brine, dried over Na2SO4, filtered, and concentrated and purified by ISCO Companion (0-40% EtOAc/hexane; 80g column). N-(2-bromophenyl)-1,1,1-trifluoromethanesulfonamide (4A) (189 mg, 0.622 mmol, 36% yield) was obtained as a brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.61-7.65 (2 H, m), 7.37 (1 H, td, J=7.9, 1.4 Hz), 7.17 (1 H, td, J=7.8, 1.4 Hz). MS(ES): m/z = 304 [M-H]-.
    • 4B. 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine
  • Figure imgb0147
  • 4-Bromo-N1,N1-diisobutylbenzene-1,2-diamine (560 mg, 1.87 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (550 mg, 2.43 mmol), PdCl2(dppf)-CH2Cl2Adduct (46 mg, 0.056 mmol), and potassium acetate (551 mg, 5.61 mmol) were combined in a 2 dram vial, and DMSO (Volume: 3 mL) was added. The vial was evacuated and filled with argon 3x, then heated at 80 °C for 3h, cooled to RT and the contents purified by ISCO Companion (0-20% EtOAc/hexane; 80g column). 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (355 mg, 1.068 mmol, 57% yield) was obtained as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.12 - 7.22 (2 H, m), 7.01 - 7.08 (1 H, m), 3.74 (4 H, s), 2.64 (4 H, d, J=7.3 Hz), 1.69 - 1.85 (2 H, m), 1.02 (6 H, s), 0.89 (12 H, d, J=6.6 Hz). MS(ES): m/z = 265 [M+H-C5H8]+.
    • 4C. N-(3'-Amino-4'-(diisobutylamino)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide
  • Figure imgb0148
  • 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (71 mg, 0.21 mmol), N-(2-bromophenyl)-1,1,1-trifluoromethanesulfonamide (50 mg, 0.16 mmol), PdCl2(dppf)-CH2Cl2Adduct (13.43 mg, 0.016 mmol), and potassium phosphate, tribasic (0.247 mL, 0.493 mmol) were added to a 2 dram vial and evacuated and filled with argon 3x. The mixture was suspended in 1 mL of dioxane and heated at 80 °C for 3h, cooled to rt and purified via ISCO Companion (0-20% EtOAc/hexane; 25g column). N-(3'-Amino-4'-(diisobutylamino)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide (30 mg, 0.068 mmol, 41% yield) was obtained as a purple gum. 1H NMR (400 MHz, CDCl3) δ ppm 7.64(d, 1H, J = 8.8 Hz); 7.26-7.41(m, 3H); 7.18(d, 1 H, J = 7.9 Hz); 6.62-6.69(m, 2H); 2.69(d, 4H, J = 7.3 Hz); 1.78-1.91(m, 2H); 0.98(d, 12H, J = 6.6 Hz). MS(ES): m/z = 444 [M+H]+.
    • 4. N-(4'-(Diisobutylamino)-3'-(3-p-tolylureido)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide
  • Figure imgb0149
  • N-(3'-Amino-4'-(diisobutylamino)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide (4C) (30 mg, 0.068 mmol) was taken up in THF (Volume: 2 mL) and 1-isocyanato-4-methylbenzene (0.011 mL, 0.088 mmol) was added. The reaction was stirred at rt overnight, and then solvent removed in vacuo. The reaction mixture was purified by prep. HPLC C18 (PHENOMENEX® Luna S5 ODS 21 x 100 mm, 10mM NH4OAc in MeOH/H2O gradient) to afford N-(4'-(diisobutylamino)-3'-(3-p-tolylureido)biphenyl-2-yl)-1,1,1-trifluoromethanesulfonamide(23 mg, 58%) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 7.86 (1 H, d, J=2.0 Hz), 7.33 - 7.40 (2 H, m), 7.19 - 7.33 (5 H, m), 7.13 - 7.18 (1 H, m), 7.10 (2 H, d, J=8.1 Hz), 2.72 (4 H, d, J=7.0 Hz), 2.29 (3 H, s), 1.69 - 1.84 (2 H, m), 0.91 (12 H, d, J=6.8 Hz). MS(ES): m/z = 577 [M+H]+.
    • Example 5 1-(4-(Diisobutylamino)-5-fluoro-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0150
    • 5A. 5-Bromo-2-(diisobutylamine)-3-fluorobenzoic acid
  • Figure imgb0151
  • A solution of 5-bromo-2,3-difluorobenzoic acid (0.75 g, 3.16 mmol) in NMP (Volume: 0.4 mL) was treated with diisobutylamine (1.636 g, 12.66 mmol) and heated to 145 °C for 17h. Chromatography on silica gel (gradient elution with EtOAc-hexanes-1%HOAc) afforded 0.22g (20%) of 5-bromo-2-(diisobutylamine)-3-fluorobenzoic acid as an off-white solid plus some mixed fractions. Concentration and silica gel chromatography on the mixed fractions afforded a further 0.3g of material. MS(ES): m/z = 348 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.51(br.s, 1 H); 7.69(dd, 1 H, J = 11.9, 2.4 Hz); 7.61(br. s, 1H); 2.88(d, 4H, J = 6.6 Hz); 1.65-1.77(m, 2H); 0.82(d, 12H, J = 6.6 Hz).
    • 5B. 4-Bromo-6-fluoro-N1,N1-diisobutylbenzene-1,2-diamine
  • Figure imgb0152
  • A solution of 5-bromo-2-(diisobutylamino)-3-fluorobenzoic acid (5A) (0.3 g, 0.87 mmol) and triethylamine (0.145 mL, 1.04 mmol) in THF (Volume: 5 mL) was treated with diphenyl phosphorazidate (0.26 g, 0.95 mmol) and stirred 30 min. at RT. The solution was then treated with tert-butanol (2.5 mL, 26 mmol) and heated to reflux. The reaction was stirred overnight at 65 °C then cooled, diluted with ether, and washed with aq. HOAc then aq. sodium bicarbonate. The organic phase was dried, stripped, and redissolved in 4 mL of 4M HCl/dioxane. The resulting solution was stirred 1.5h at RT then concentrated to afford an oil. LCMS indicated some t-butyl carbamate remained, so the oil was dissolved in 4 mL of HCl/dioxane and stirred 3h at RT. The reaction was concentrated to near dryness under reduced pressure. Addition of a few drops of methanol afforded a precipitate which was filtered, rinsed with 30% ether-hexanes, and air-dried to afford 0.039 g (14%) of 4-bromo-6-fluoro- N1,N1-diisobutylbenzene-1,2-diamine as a colorless solid. Prep. HPLC (Axia 30 x 100 mm column, MeOH-water-TFA gradient) on the mother liquor afforded a further 0.04 g of material. MS(ES): m/z = 319 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.67 (1H, dd, J= 2.2, 1.2 Hz), 6.50 (1 H, dd, J=11.4, 2.2 Hz), (NH2 obscured by broad water peak); 2.57-2.72 (4 H, m), 1.53-1.63 (2 H, m), 0.81-0.87 (12 H, m).
    • 5C. 1-(5-Bromo-2-(diisobutylamino)-3-fluorophenyl)-3-p-tolylurea
  • Figure imgb0153
  • A solution of 4-bromo-6-fluoro-N1,N1-diisobutylbenzene-1,2-diamine (5B) (0.065 g, 0.205 mmol) in THF (Volume: 1 mL) was treated with 1-isocyanato-4-methylbenzene (0.038 g, 0.287 mmol) and placed under nitrogen. The reaction was stirred 30 min. at 50 °C. An additional 0.04 g of p-tolylisocyanate was added, and the reaction was stirred 2h longer at 50 °C. The reaction was cooled, treated with 0.03 mL of N,N-dimethylethylenediamine, and chromatographed on silica gel (gradient elution with EtOAc-hexanes). Concentration of the appropriate fractions afforded 0.85g (92%) of 1-(5-bromo-2-(diisobutylamino)-3-fluorophenyl)-3-p-tolylurea as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.57(s, 1 H); 8.18-8.22(m, 2H); 7.34(d, 2H, J = 8.6 Hz); 7.10(d, 2H, J = 8.4 Hz); 7.07(dd, 1 H, J = 11.4, 2.2 Hz); 2.73-2.84(br. m, 4H); 2.24(s, 3H); 1.54-1.64(m, 2H); 0.82(d, 6H, J = 6.6 Hz). MS(ES): m/z = 452 [M+H]+.
    • 5. 1-(4-(Diisobutylamino)-5-fluoro-2'-(1H-tetrazol-5-yl)biphenyl-3yl)-3-p-tolylurea
  • Figure imgb0154
  • To a mixture of 2-(1H-tetrazol-5-yl)phenylboronic acid (0.025 g, 0.133 mmol) and 1-(5-bromo-2-(diisobutylamino)-3-fluorophenyl)-3-p-tolylurea (5C) (0.03 g, 0.067 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.70 mg, 6.66 µmol) in degassed DMF (Volume: 1 mL) was added aq. potassium carbonate (0.222 mL, 0.333 mmol). The mixture was placed under nitrogen and heated at 90 °C for 1h. The reaction was cooled, brought to pH 4 with glacial HOAc, filtered, and purified by prep. HPLC (Axia 30 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate fraction afforded 0.027 g (79%) of 1-(4-(diisobutylamino)-5-fluoro-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.47(s, 1 H); 8.14(s, 1H); 7.82(d, 1H, J = 1.5 Hz); 7.57-7.73(m, 4H); 7.34(d, 2H, J = 8.4 Hz); 7.11(d, 2H, J = 8.1 Hz); 6.44(dd, 1 H, J = 12.8, 2.0 Hz); 2.81(d, 4H, J = 5.7); 2.26(s, 3H); 1.60-1.70(m, 2H); 0.86(d, 12H, J = 6.6 Hz). MS(ES): m/z = 516 [M+H]+.
    • Example 6 4'-(Diisobutylamino)-3'-fluoro-5'-(3-p-tolylureido)biphenyl-2-carboxylic acid
  • Figure imgb0155
  • The title compound was prepared from 5C and 2-carboxyphenylboronic acid by the procedure used to convert 5C into 5. MS(ES): m/z = 492 [M+H]+. HPLC Tr: 13.02d.
    • Example 7 4'-(2-tert-Butylphenoxy)-4-ethoxy-3'-(3-p-tolylureido)biphenyl-3-carboxylic acid
  • Figure imgb0156
    • 7A. 3'-Amino-4'-(diisobutylamino)biphenyl-2-carbonitrile
  • Figure imgb0157
  • 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (4B) (356 mg, 1.07 mmol, 2-bromobenzonitrile (150 mg, 0.824 mmol), PdCl2(dppf)-CH2Cl2Adduct (67.3 mg, 0.082 mmol), and potassium phosphate, tribasic (1.24 mL, 2.48 mmol) were added to a 2 dram vial and evacuated and filled with argon 3x. The mixture was heated at 80 °C for 3h. An additional 0.05 eq. PdCl2(dppf)-CH2Cl2Adduct and 75 mg bromobenzonitrile were added and heating was continued for 3h. The reaction was cooled to rt and purified via ISCO Companion (EtOAc/hexane gradient) to afford 3'-amino-4'-(diisobutylamino)biphenyl-2-carbonitrile (289 mg, >quantitative yield) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ ppm 7.76(dd, 1H, J = 7.0, 1.1 Hz); 7.63(td, 1H, J = 7.6, 1.3 Hz); 7.53(dd, 1 H, J = 7.7, 0.9 Hz); 7.41(td, 1H, J = 7.5, 1.1 Hz); 7.18(d, 1h, J = 8.6 Hz); 6.92-6.97(m, 2H); 4.2-4.3(br. s, 2H); 2.69(d, 4H, J = 7.3 Hz); 1.79-1.91(m, 2H); 0.96(d, 12H, J = 6.8 Hz). MS(ES): m/z = 322 [M+H]+.
    • 7B: N4,N4-Diisobutyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine
  • Figure imgb0158
  • A solution of 3'-amino-4'-(diisobutylamino)biphenyl-2-carbonitrile (7A) (148 mg, 0.460 mmol) and azidotributyltin (0.883 mL, 3.22 mmol) in toluene (Volume: 3 mL) was heated at 110 °C for 5h. The reaction was cooled to rt and purified via ISCO Companion (EtOAc/hexane gradient with 1% AcOH). N4,N4-Diisobutyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (163 mg, 97% yield) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm (all lines are somewhat broad.) 7.96(d, 1H, J = 7.5 Hz); 7.53-7.64(m, 2H); 7.47(d, 1 H, J = 7.3 Hz); 7.08(d, 1H, J - 7.3 Hz); 7.00(s, 1H); 6.65(d, 1H, J = 7.7 Hz); 2.98-3.10(br. d, 4H, coupling unresolved); 1.88-1.98(m, 2H); 0.91(d, 12H, J = 6.6 Hz). MS(ES): m/z = 365 [M+H]+.
    • 7. 1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(thiazol-2-yl)urea
  • Figure imgb0159
  • N4,N4-Diisobutyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (7B) (20 mg, 0.055 mmol) was taken up in DCM (1 mL) and Et3N (0.038 mL, 0.274 mmol) and 4-nitrophenyl carbonochloridate (13 mg, 0.066 mmol) were added. The reaction was stirred at rt for 1h, an additional 5 eq. of Et3N and 1.2 eq. 4-nitrophenyl carbonochloridate were added, and the reaction was stirred overnight. The reaction was diluted with DCM and washed with 0.1M HCl, then brine. The organic phase was dried over Na2SO4, filtered and concentrated. The yellow residue was taken up in DMF (1.000 mL) and Et3N (0.038 mL, 0.274 mmol) and thiazol-2-amine (8.2 mg, 0.082 mmol) were added. The reaction was stirred 3h at RT then purified by prep. HPLC (C18 PHENOMENEX® Luna S5 ODS 21 x 100 mm, 10mM NH4OAc, MeOH-H2O gradient). Concentration of the appropriate fractions afforded 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(thiazol-2-yl)urea (8.4 mg, 31% yield) as an off-white solid. MS(ES): m/z = 491 [M+H]+. HPLC Tr: 2.23°.
    • Example 8 4'-(Benzyl(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0160
    • 8A. 4-Bromo-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • Figure imgb0161
  • To a solution of 4-bromo-1-fluoro-2-nitrobenzene (0.440 g, 2 mmol) in DMF (1mL) was added Hunig's base followed by 3,3,3-trifluoropropan-1-amine, HCl (0.419 g, 2.80 mmol). The solution was stirred 1h at 90 °C then cooled and poured into 40 ml of water. The mixture was rapidly stirred while the pH was adjusted to ∼5 with glacial HOAc. Product precipitated and was filtered, rinsed with water, and air-dried to afford 4-bromo-2-nitro-N-(3,3,3-trifluoropropyl)aniline (0.6 g, 91% yield) as an orange powder. Spectra was consistent with the proposed nitroaniline at a purity of >95%. MS(ES): m/z = 313 [M+H]+, HPLC Tr: 2.14p.
    • 8B. N-Benzyl-4-bromo-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • Figure imgb0162
  • To a solution of 4-bromo-2-nitro-N-(3,3,3-trifluoropropyl)aniline (8A) (0.1 g, 0.319 mmol) in DMF (2 mL) was added sodium hydride (0.038 g, 0.958 mmol). The mixture was stirred 2 min. at RT then treated with (bromomethyl)benzene (0.057 mL, 0.479 mmol). The reaction was stirred 1h at RT then quenched with aq. HOAc. This mixture was extracted with ether, and the organic extract was dried, stripped and purified by ISCO chromatography (gradient elution with EtOAc-hexanes) to afford N-benzyl-4-bromo-2-nitro-N-(3,3,3-trifluoropropyl)aniline (0.11 g, 81% yield) as an orange oil at a purity of >95%. MS(ES): m/z = 405 [M+H]+, HPLC Tr: 2.71q.
    • 8C. N1-Benzyl-4-bromo-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine
  • Figure imgb0163
  • To a solution of N-benzyl-4-bromo-2-nitro-N-(3,3,3-trifluoropropyl)aniline (8B) (0.1 g, 0.248 mmol) in ethanol (6 mL) was added 1 mL of water followed by ammonium chloride (0.199 g, 3.72 mmol). The mixture was stirred 10 min. at RT then treated with zinc (0.243 g, 3.72 mmol). This mixture was stirred 30 min. at RT, diluted with dichloromethane, and filtered. The filtrate was washed with water, dried, and stripped to afford N1-benzyl-4-bromo-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (8C) (0.09 g, 92% yield) as an amber oil. Spectra was consistent with the proposed aniline at a purity of ∼95%. MS(ES): m/z = 373 [M+H]+, HPLC Tr: 4.53l.
    • 8D. 1-(2-(Benzyl(3,3,3-trifluoropropyl)amino)-5-bromophenyl)-3-(p-tolyl)urea
  • Figure imgb0164
  • To a solution of N1-benzyl-4-bromo-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (8C) (0.086 g, 0.23 mmol) in THF (1 mL) was added 1-isocyanato-4-methylbenzene (0.040 g, 0.299 mmol). The solution was stirred 1h at 55 °C then cooled to RT, treated with 0.02 mL of N,N-dimethylethylenediamine, and purified by ISCO chromatography (gradient elution with EtOAc-hexanes) to afford 0.1 g (86%) of 1-(2-(benzyl(3,3,3-trifluoropropyl)amino)-5-bromophenyl)-3-(p-tolyl)urea as a white powder. MS(ES): m/z = 508 [M+H]+, HPLC Tr: 2.79q.
    • 8. 4'-(Benzyl(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0165
  • To a suspension of 2-boronobenzoic acid (0.016 g, 0.099 mmol) and 1-(2-(benzyl(3,3,3-trifluoropropyl)amino)-5-bromophenyl)-3-(p-tolyl)urea (8D) (0.025 g, 0.049 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.71 mg, 4.94 µmol) in degassed DMF (1 mL) was added aq. potassium carbonate (0.165 mL, 0.247 mmol). The mixture was placed under nitrogen and heated at 95 °C for 3h. The reaction was cooled to 60 °C, brought to pH4 with glacial HOAc, filtered, and purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 150 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 4'-(benzyl(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid (0.015 g, 52.7% yield). MS(ES): m/z = 548 [M+H]+, HPLC Tr: 4.72l.
    • Example 9 4'-(Benzyl(3,3,3-trifluoropropyl)amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0166
  • To a suspension of 8D (0.025 g, 0.049 mmol) and 2-borono-4-fluorobenzoic acid (0.018 g, 0.099 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.71 mg, 4.94 µmol) in degassed DMF (1 mL) was added aq. potassium carbonate (0.165 mL, 0.247 mmol). The mixture was placed under nitrogen and heated at 95°C for 3h. The reaction was cooled to 60°C, brought to pH4 with glacial HOAc, filtered, and purified by prep. HPLC (Axia Luna 30 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate fraction afforded 0.014 g (50%) of 4'-(Benzyl(3,3,3-trifluoropropyl)amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid. MS(ES): m/z = 566 [M+H]+, HPLC Tr: 4.86l.
    • Example 10 1-(4-(Benzyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0167
  • The title compound was prepared from 8D and 2-tetrazolylphenylboronic acid by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 572 [M+H]+, HPLC Tr: 2.64q.
    • Example 11 4'-((3-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0168
    • 11A. 4-Bromo-N-(3-chlorobenzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • The title compound was prepared from 8A and 3-chlorobenzyl bromide by the general procedure used for the conversion of 8A to 8B. MS(ES): m/z = 439 [M+H]+, HPLC Tr: 4.951.
    • 11B. 4-Bromo-N1-(3-chlorobenzyl)-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine
  • The title compound was prepared from 11A by the general procedure used for the conversion of 8B to 8C. MS(ES): m/z = 409 [M+H]+, HPLC Tr: 4.74l.
    • 11C. 1-(5-Bromo-2-((3-chlorobenzyl)(3,3,3-trifluoropropyl)amino)phenyl)-3-(p-tolyl)urea
  • The title compound was prepared from 11B by the general procedure used for the conversion of 8C to 8D. MS(ES): m/z = 542 [M+H]+, HPLC Tr: 2.84q.
    • 11. 4'-((3-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • The title compound was prepared from 11C by the general procedure used for the conversion of 8D to 8. MS(ES): m/z = 582 [M+H]+, HPLC Tr: 4.83l.
    • Example 12 4'-((3-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0169
  • The title compound was prepared from 11C and 2-carboxy-5-fluorophenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 600 [M+H]+, HPLC Tr: 4.94l.
    • Example 13 1-(4-((3-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0170
  • The title compound was prepared from 11C and 2-tetrazolylphenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 606 [M+H]+, HPLC Tr: 4.81l.
    • Example 14 4'-((4-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0171
    • 14A. 4-Bromo-N-(4-chlorobenzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • The title compound was prepared from 8A and 4-chlorobenzyl bromide by the general procedure used for the conversion of 8A to 8B. MS(ES): m/z = 439 [M+H]+, HPLC Tr: 4.99l.
    • 14B. 4-Bromo-N1-(4-chlorobenzyl)-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine
  • The title compound was prepared from 14A by the general procedure used for the conversion of 8B to 8C. MS(ES): m/z = 409 [M+H]+, HPLC Tr: 4.77l.
    • 14C. 1-(5-Bromo-2-((4-chlorobenzyl)(3,3,3-trifluoropropyl)amino)phenyl)-3-(p-tolyl)urea
  • The title compound was prepared from 14B by the general procedure used for the conversion of 8C to 8D. MS(ES): m/z = 542 [M+H]+, HPLC Tr: 511l.
    • 14. 4'-((4-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • The title compound was prepared from 14C by the general procedure used for the conversion of 8D to 8. MS(ES): m/z = 582 [M+H]+, HPLC Tr: 4.87l
    • Example 15 4'-((4-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0172
  • The title compound was prepared from 14C and 2-carboxy-5-fluorophenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 600 [M+H]+, HPLC Tr: 4.97l.
    • Example 16 1-(4-((4-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0173
  • The title compound was prepared from 14C and 2-tetrazolylphenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 606 [M+H]+, HPLC Tr: 2.98r .
    • Example 17 4'-((2-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0174
    • 17A. 4-Bromo-N-(2-chlorobenzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • The title compound was prepared from 8A and 2-chlorobenzyl bromide by the general procedure used for the conversion of 8A to 8B. MS(ES): m/z = 439 [M+H]+, HPLC Tr: 4.94l.
    • 17B. 4-Bromo-N1-(2-chlorobenzyl)-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine
  • The title compound was prepared from 17A by the general procedure used for the conversion of 8B to 8C. MS(ES): m/z = 409 [M+H]+, HPLC Tr: 4.78l.
    • 17C. 1-(5-Bromo-2-((2-chlorobenzyl)(3,3,3-trifluoropropyl)amino)phenyl)-3-(p-tolyl)urea
  • The title compound was prepared from 14B by the general procedure used for the conversion of 8C to 8D. MS(ES): m/z = 542 [M+H]+, HPLC Tr: 3.19r.
    • 17. 4'-((2-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • The title compound was prepared from 17C by the general procedure used for the conversion of 8D to 8. MS(ES): m/z = 582 [M+H]+, HPLC Tr: 4.85l.
    • Example 18 4'-((2-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0175
  • The title compound was prepared from 17C and 2-carboxy-5-fluorophenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 600 [M+H]+, HPLC Tr: 3.04r .
    • Example 19 1-(4-((2-Chlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0176
  • The title compound was prepared from 17C and 2-tetrazolylphenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 606 [M+H]+, HPLC Tr: 4.81l .
    • Example 20 4'-(Benzyl(2,2-difluoroethyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0177
    • 20A. 4-Bromo-N-(4-chlorobenzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • The title compound was prepared from the nitro intermediate iiik and benzyl bromide by the general procedure used for the conversion of 8A to 8B. MS(ES): m/z = 371 [M+H]+, HPLC Tr: 2.58q.
    • 20B. N1-Benzyl-4-bromo-N1-(2,2-difluoroethyl)benzene-1,2-diamine
  • The title compound was prepared from 20A by the general procedure used for the conversion of 8B to 8C. MS(ES): m/z = 343 [M+H]+, HPLC Tr: 4.15l.
    • 20C. 1-(2-(Benzyl(2,2-difluoroethyl)amino)-5-bromophenyl)-3-(p-tolyl)urea
  • The title compound was prepared from 20B by the general procedure used for the conversion of 8C to 8D. MS(ES): m/z = 476 [M+H]+, HPLC Tr: 2.68q.
    • 20. 4'-(Benzyl(2,2-difluoroethyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • The title compound was prepared from 20C by the general procedure used for the conversion of 8D to 8. MS(ES): m/z = 516 [M+H]+, HPLC Tr: 2.11k.
    • Example 21 4'-(Benzyl(2,2-difluoroethyl)amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0178
  • The title compound was prepared from 20C and 2-carboxy-5-fluorophenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 534 [M+H]+, HPLC Tr: 2.16k.
    • Example 22 1-(4-(Benzyl(2,2-difluoroethyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0179
  • The title compound was prepared from 20C and 2-tetrazolylphenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 540 [M+H]+, HPLC Tr: 2.07k.
    • Example 23 5-Fluoro-4'-(isobutyl(prop-2-yn-1-yl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0180
    • 23A. 4-Bromo-N-isobutyl-2-nitro-N-(prop-2-yn-1-yl)aniline
  • The title compound was prepared from the nitro intermediate iiias and propargyl bromide by the general procedure used for the conversion of 8A to 8B. MS(ES): m/z = 313 [M+H]+, HPLC Tr: 4.61l.
    • 23B. 4-Bromo-N1-isobutyl-N1-(prop-2-yn-1-yl)benzene-1,2-diamine
  • The title compound was prepared from 23A by the general procedure used for the conversion of 8B to 8C. MS(ES): m/z = 283 [M+H]+, HPLC Tr: 213p.
    • 23C. 1-(5-Bromo-2-(isobutyl(prop-2-yn-1-yl)amino)phenyl)-3-(p-tolyl)urea
  • The title compound was prepared from 23B by the general procedure used for the conversion of 8C to 8D. MS(ES): m/z = 416 [M+H]+, HPLC Tr: 2.76q.
    • 23. 5-Fluoro-4'-(isobutyl(prop-2-yn-1-yl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • The title compound was prepared from 23C and 2-carboxy-5-fluorophenylboronic acid by the general procedure used for the conversion of 8D to 8. MS(ES): m/z = 474 [M+H]+, HPLC Tr: 2.66q.
    • Example 24 1-(4-(Isobutyl(prop-2-yn-1-yl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0181
  • The title compound was prepared from 23C and 2-tetrazolylphenylboronic acid by the general procedure for the conversion of 8D to 8. MS(ES): m/z = 480 [M+H]+, HPLC Tr: 2.55q.
    • Example 25 1-(4-(Diisobutylamino)-2-fluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0182
    • 25A. 3-Fluoro-N,N-diisobutyl-2-nitroaniline
  • Figure imgb0183
  • To a stirred solution of 1,3-difluoro-2-nitrobenzene (0.955 g, 6 mmol) in NMP (2 mL) was added Hunig's Base (1.153 mL, 6.60 mmol) followed by diisobutylamine (0.775 g, 6.00 mmol). The solution was stirred 30 min. at 100 °C, after which time it was still pale yellow with TLC showing a tiny new spot. The temperature was raised to 125 °C, stirring was continued 2h longer, and overnight at 110 °C. LCMS shows ∼10% SM and essentially none of the bis-adduct; 0.1 mL more diisobutylamine was added, and the reaction was stirred 1h longer at 125 °C. The reaction was cooled and poured into aq. HOAc. This mixture was extracted with 1:1 ether-heptane, and the organic extract was washed with sat'd aq. sodium bicarbonate, dried, and stripped to afford 3-fluoro-N,N-diisobutyl-2-nitroaniline (1.5 g, 89% yield) as a dark oil. MS(ES): m/z = 269 [M+H]+. HPLC Tr: 4.83l.
    • 25B. 4-Bromo-3-fluoro-N,N-diisobutyl-2-nitroaniline
  • Figure imgb0184
  • To a stirred, cooled (0 °C) solution of 3-fluoro-N,N-diisobutyl-2-nitroaniline (25A) (0.268 g, 1 mmol) in DMF (3 mL) was added N-bromosuccinimide (0.178 g, 1.000 mmol). The solution was warmed to RT, stirred an additional 15 min., and TLC taken. Most of the UV+ material was a new spot at slightly higher Rf (∼0.7 in 10% ether-hexanes) than the ∼10-20% SM which remains. A much smaller spot was present further down the plate. An additional 30 mg of NBS was added, and the reaction was stirred 30 min. longer then partially concentrated. Flash chromatography (gradient elution with ether-hexanes afforded 4-bromo-3-fluoro-N,N-diisobutyl-2-nitroaniline (0.32 g, 88% yield) as an orange oil. MS(ES): m/z = 349 [M+H]+. HPLC Tr: 2.89q.
    • 25C. 4-Bromo-3-fluoro-N1,N1-diisobutylbenzene-1,2-diamine
  • Figure imgb0185
  • To a solution of 4-bromo-3-fluoro-N,N-diisobutyl-2-nitroaniline (25B) (0.28 g, 0.806 mmol) in ethanol (8 mL) was added 2 mL of water followed by ammonium chloride (0.259 g, 4.84 mmol). The resulting mixture was stirred 5 min. at RT then treated with zinc (0.316 g, 4.84 mmol). This mixture was stirred vigorously for 30 min. then diluted with dichloromethane and filtered. The filtrate was washed with water, dried, and stripped to afford 4-bromo-3-fluoro-N1,N1-diisobutylbenzene-1,2-diamine (0.25 g, 98% yield) as a brown oil. Spectra was consistent with the proposed aniline at the stated level of purity. MS(ES): m/z = 319 [M+H]+. HPLC Tr: 5.10l.
    • 25D. 1-(3-Bromo-6-(diisobutylamino)-2-fluorophenyl)-3-(p-tolyl)urea
  • Figure imgb0186
  • A solution of crude 4-bromo-3-fluoro-N1,N1-diisobutylbenzene-1,2-diamine (0.254 g, 0.8 mmol) was dissolved in THF (1 mL), treated with 1-isocyanato-4-methylbenzene (0.138 g, 1.040 mmol), and stirred 18h at 45 °C. The reaction was quenched with 0.04 mL of N,N-dimethylethylenediamine and purified by flash chromatography (gradient elution with EtOAc-hexanes). Concentration of the appropriate fractions afforded 1-(3-bromo-6-(diisobutylamino)-2-fluorophenyl)-3-(p-tolyl)urea (0.16 g, 40.0% yield) as a tan solid. MS(ES): m/z = 452 [M+H]+. HPLC Tr: 2.74q.
    • 25. 1-(3-Bromo-6-(diisobutylamino)-2-fluorophenyl)-3-(p-tolyl)urea
  • Figure imgb0187
  • A suspension of (2-(1H-tetrazol-5-yl)phenyl)boronic acid (0.025 g, 0.133 mmol) and 1-(3-bromo-6-(diisobutylamino)-2-fluorophenyl)-3-(p-tolyl)urea (25D) (0.03 g, 0.067 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.70 mg, 6.66 µmol) in degassed DMF (1.5 mL) was treated with aq. potassium carbonate (0.222 mL, 0.333 mmol). The reaction was heated at 95 °C for 2h then cooled to RT and stirred overnight. The reaction was treated with glacial HOAc to pH3 then filtered and purified by prep. HPLC. (Axia Luna 30 x 100 mm column, MeOH-water-TFA gradient). The appropriate fraction was concentrated to afford 1-(4-(diisobutylamino)-2-fluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea (0.006 g, 16% yield) as a white powder. MS(ES): m/z = 516 [M+H]+. HPLC Tr: 12.61d.
    • Example 26 4'-(Diisobutylamino)-2'-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0188
  • The title compound was prepared from 25D and 2-carboxyphenylboronic acid by the general procedure for the preparation of 25. MS(ES): m/z = 492 [M+H]+, HPLC Tr: 12.43d.
    • Example 27 1-(4-(Isobutyl(4,4,4-trifluoro-2-methylbutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0189
    • 27A. (+/-)-4,4,4-Trifluoro-N-isobutyl-2-methylbutanamide
  • Figure imgb0190
  • A solution of 2-methylpropan-1-amine (0.285 g, 3.90 mmol) and 4,4,4-trifluoro-2-methylbutanoic acid (0.468 g, 3 mmol) in DMF (8 mL) was treated with triethylamine (0.544 mL, 3.90 mmol) followed by BOP (1.460 g, 3.30 mmol). The solution was stirred 18h at RT then diluted with ether and washed with 0.5 M aq. HCl and then saturated aq. sodium bicarbonate. The organic phase was dried and stripped to afford 4,4,4-trifluoro-N-isobutyl-2-methylbutanamide (0.6 g, 90% yield) as a waxy white solid. MS(ES): m/z = 212 [M+H]+. HPLC Tr: 1.60p.
    • 27B. (+/-)-4,4,4-Trifluoro-N-isobutyl-2-methylbutan-1-amine
  • Figure imgb0191
  • To a solution of lithium aluminum hydride (7.50 mL, 7.50 mmol) in THF was added 4,4,4-trifluoro-N-isobutyl-2-methylbutanamide (27A) (0.528 g, 2.5 mmol). The suspension was brought to reflux and stirred for 6h. The reaction was cooled and stirred overnight at RT. The reaction was quenched using the method of Fieser, and treated with 10 mL more THF, and MgSO4 and then stirred 1h at RT. The reaction was filtered and stripped to afford 4,4,4-trifluoro-N-isobutyl-2-methylbutan-1-amine, 0.5 tetrahydrofuran (0.57 g, 93% yield) as a colorless oil. MS(ES): m/z = 198 [M+H]+. HPLC Tr: 1.27p.
    • 27C. (+/-)-4-Bromo-N-isobutyl-2-nitro-N-(4,4,4-trifluoro-2-methylbutyl)aniline
  • Figure imgb0192
  • To a solution of 4-bromo-1-fluoro-2-nitrobenzene (0.220 g, 1 mmol) and 4,4,4-trifluoro-N-isobutyl-2-methylbutan-1-amine (27B), 0.5 tetrahydrofuran (0.327 g, 1.400 mmol) in N-methyl-2-pyrrolidinone (0.3 mL) was added Hunig's Base (0.210 mL, 1.200 mmol). The reaction was stirred at 130 °C for 18h. The reaction was cooled to RT, diluted with ether and washed with 10% aq. HOAc then aq. sodium bicarbonate. The organic phase was dried and stripped to afford 4-bromo-N-isobutyl-2-nitro-N-(4,4,4-trifluoro-2-methylbutyl)aniline (0.38 g, 86% yield) as a dark orange oil. MS(ES): m/z = 399 [M+H]+. HPLC Tr: 5.05l.
    • 27D. (+/-)-4-Bromo-N1-isobutyl-N1-(4,4,4-trifluoro-2-methylbutyl)benzene-1,2-diamine
  • Figure imgb0193
  • The title compound was prepared from 27C by the procedure used for the conversion of 8B to 8C. MS(ES): m/z = 369 [M+H]+. HPLC Tr: 2.76q.
    • 27E. 1-(5-Bromo-2-(isobutyl(4,4,4-trifluoro-2-methylbutyl)amino)phenyl)-3-(p-tolyl)urea
  • Figure imgb0194
  • The title compound was prepared from 27D at 50 °C by the procedure used for the conversion of 8C to 8D. MS(ES): m/z = 502 [M+H]+. HPLC Tr: 3.25r.
    • 27. 1-(4-(Isobutyl(4,4,4-trifluoro-2-methylbutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb0195
  • The title compound was prepared from 27E by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 566 [M+H]+. HPLC Tr: 2.70q.
    • Example 28 4'-(Isobutyl(4,4,4-trifluoro-2-methylbutyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb0196
  • The title compound was prepared from 27E and 2-carboxyphenylboronic acid by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 542 [M+H]+. HPLC Tr: 2.71q.
    • Example 29 1-(4-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0197
    • 29A. N-Cyclohexylisobutyramide
  • Figure imgb0198
  • To a stirred, cooled (0 °C) solution of cyclohexanamine (1.091 g, 11.00 mmol) and triethylamine (1.214 g, 12.00 mmol) in THF (Volume: 10 mL) was added isobutyryl chloride (1.066 g, 10 mmol). The resulting slurry was stirred 30 min., warming to RT then diluted with 1:1 ether-hexanes. The resulting mixture was washed with aq. HCl then sat'd aq. sodium bicarbonate, dried, and stripped to afford N-cyclohexylisobutyramide as a colorless solid. MS(ES): m/z = 170 [M+H]+. HPLC Tr: 2.611.
    • 29B. N-(1,1-Dideutero-2-methylpropyl)cyclohexanamine
  • Figure imgb0199
  • The title compound was prepared from 29A and lithium aluminum deuteride by the procedure used for the conversion of 27A to 27B. MS(ES): m/z = 158 [M+H]+. HPLC Tr: 1.56p.
    • 29C. 4-Bromo-N-cyclohexyl-N-(1,1-dideutero-2-methylpropyl)-2-nitroaniline
  • Figure imgb0200
  • The title compound was prepared from 29B at 140 °C by the procedure used for the conversion of 27B to 27C. MS(ES): m/z = 359 [M+H]+. HPLC Tr: 3.74q.
    • 29D. 4-Bromo-N1-cyclohexyl-N1-(1,1-difluoro-2-methylpropyl)benzene-1,2-diamine
  • Figure imgb0201
  • The title compound was prepared from 29C by the procedure used for the conversion of 8B to 8C. MS(ES): m/z = 327 [M+H]+. HPLC Tr: 2.86q.
    • 29E. 1-(5-Bromo-2-(cyclohexyl(1,1-dideutero-2-methylpropyl)amino)phenyl)-3-p-tolylurea
  • Figure imgb0202
  • The title compound was prepared from 29D at 55 °C by the procedure used for the conversion of 8C to 8D. MS(ES): m/z = 462 [M+H]+. HPLC Tr: 5.361.
    • 29. 1-(4-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0203
  • The title compound was prepared from 29E at 100 °C by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 526 [M+H]+. HPLC Tr: 13.01d.
    • Example 30 4'-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-3'-(3-p-tolylureido)biphenyl-2-carboxylic acid
  • Figure imgb0204
  • The title compound was prepared from 29E and 2-carboxyphenylboronic acid at 100 °C by the procedure used for the conversion of 8E to 8. MS(ES): m/z = 502 [M+H]+. HPLC Tr: 12.64d.
    • Example 31 4'-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-5-fluoro-3'-(3-p-tolylureido)biphenyl-2-carboxylic acid
  • Figure imgb0205
  • The title compound was prepared from 29E and 2-carboxy-5-fluorophenylboronic acid at 100 °C by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 520 [M+H]+. HPLC Tr: 13.04d.
    • Example 32 1-(4-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
  • Figure imgb0206
    • 32A. 1-(5-Bromo-2-(cyclohexyl(1,1-dideutero-2-methylpropyl)amino)phenyl)-3-(2-fluorophenyl)urea
  • Figure imgb0207
  • The title compound was prepared from 29D and 2-fluorophenylisocyanate at 55 °C by the procedure used for the conversion of 8C to 8D. MS(ES): m/z = 466 [M+H]+. HPLC Tr: 3.43q.
    • 32. 1-(4-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
  • Figure imgb0208
  • The title compound was prepared from 32A at 100 °C by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 530 [M+H]+. HPLC Tr: 3.05q.
    • Example 33 4'-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-3'-(3-(2-fluorophenyl)ureido)biphenyl-2-carboxylic acid
  • Figure imgb0209
  • The title compound was prepared from 32A and 2-carboxyphenylboronic acid at 100 °C by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 506 [M+H]+. HPLC Tr: 2.97q.
    • Example 34 4'-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-5-fluoro-3'-(3-(2-fluorophenyl)ureido)biphenyl-2-carboxylic acid
  • Figure imgb0210
  • The title compound was prepared from 32A and 2-carboxy-5-fluorophenylboronic acid at 100 °C by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 524 [M+H]+. HPLC Tr: 3.09q.
    • Example 35 4-(4-(Diisobutylamino)-3-(3-p-tolylureido)phenyl)thiophene-3-carboxylic acid
  • Figure imgb0211
    • 35A. 1-(2-(Diisobutylamino)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-3-p-tolylurea
  • Figure imgb0212
  • To a suspension of 1-(5-bromo-2-(diisobutylamino)phenyl)-3-p-tolylurea (0.432 g, 1 mmol) and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (0.294 g, 1.300 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.024 g, 0.030 mmol) in degassed DMSO (Volume: 2 mL) was added potassium acetate (0.294 g, 3.00 mmol). The mixture was placed under nitrogen and heated at 80 °C for 1.3h. The reaction temperature was raised to 90 °C, and stirring was continued for 3h. The reaction was cooled to RT, diluted with water, and extracted with ether. The organic extract was dried, stripped, and chromatographed on silica gel (gradient elution with ether-hexanes) to afford 1-(2-(diisobutylamino)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-3-p-tolylurea (0.37 g, 76% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.26 (s, 1 H), 8.22(d, 1H, J = 1.5 Hz); 7.66(s, 1H); 7.35(d, 2H, J = 8.4 Hz); 7.28(dd, 1H, J = 7.9, 1.3 Hz); 7.13(d, 1H, J = 8.1 Hz); 7.07(d, 2H, J = 8.4 Hz); 3.72(s, 4H); 2.71(d, 4H, J = 7.0 Hz); 2.24(s, 3H); 1.60-1.71(m, 2H); 0.95(s, 6H); 0.82(d, 12H, J = 6.6 Hz). MS(ES): m/z = 398 [M+H-C5H8]+.
    • 35. 4-(4-(Diisobutylamino)-3-(3-p-tolylureido)phenyl)thiophene-3-carboxylic acid
  • Figure imgb0213
  • A suspension of 4-bromothiophene-3-carboxylic acid (0.036 g, 0.17 mmol) and 1-(2-(diisobutylamino)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-3-p-tolylurea (35A) (0.04 g, 0.086 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.93 mg, 8.59 µmol) in degassed DMF (Volume: 1 mL) was treated with aq. potassium carbonate (0.29 mL, 0.43 mmol). The suspension was placed under nitrogen and heated at 95 °C for 2h. The reaction was cooled, brought to pH 5 with glacial HOAc, filtered, and purified by prep. HPLC (Axia 30 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate fraction afforded 4-(4-(diisobutylamino)-3-(3-p-tolylureido)phenyl)thiophene-3-carboxylic acid (0.008 g, 0.016 mmol, 18% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1 H), 8.23(d, 1H, J = 3.3 Hz); 7.97(d, 1H, J = 1.8 Hz); 7.83(s, 1H); 7.47(d, 1H, J = 3.3 Hz); 7.34(d, 2H, J = 8.4 Hz); 7.18(d, 1H, J = 8.4 Hz); 7.07(d, 2H, J = 8.1 Hz); 6.94(dd, 1H, J = 8.1, 1.8 Hz); 2.68(d, 4H, J = 6.8 Hz); 2.23(s, 3H); 1.61-1.76(m, 2H); 0.86(d, 12H, J = 6.6 Hz). MS(ES): m/z = 480 [M+H]+.
    • Example 36 2-(4-(Cyclohexyl(1,1-dideutero-2-methylpropyl)amino)-3-(3-(2-fluorophenyl)ureido)phenyl)thiophene-3-carboxylic acid
  • Figure imgb0214
  • The title compound was prepared from 32A and 2-boronothiophene-3-carboxylic acid at 100 °C by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 512 [M+H]+. HPLC Tr: 3.10q.
    • Example 37 1-(5-(2-(1H-Tetrazol-5-yl)phenyl)-2-(cyclohexyl(methyl)amino)pyridin-3-yl)-3-(2-fluorophenyl)urea
  • Figure imgb0215
    • 37A. 5-Bromo-N-cyclohexyl-N-methyl-3-nitropyridin-2-amine
  • Figure imgb0216
  • The title compound was prepared from 5-bromo-2-chloro-3-nitropyridine and N-methylcyclohexylamine (2.2 eq.) in DMF (~0.3 M) at 50 °C by the procedure used for the preparation of 1A. MS(ES): m/z = 316 [M+H]+. HPLC Tr: 5.011.
    • 37B. 5-Bromo-N2-cyclohexyl-N2-methylpyridine-2,3-diamine
  • Figure imgb0217
  • The title compound was prepared from 37A by the procedure used for the preparation of 1B. MS(ES): m/z = 284 [M+H]+. HPLC Tr: 2.88l.
    • 37C. 1-(5-Bromo-2-(cyclohexyl(methyl)amino)pyridin-3-yl)-3-(2-fluorophenyl)urea
  • Figure imgb0218
  • The title compound was prepared from 37B and 2-fluorophenyl isocyanate at 60 °C by the procedure used for the conversion of 8C to 8D. MS(ES): m/z = 423 [M+H]+. HPLC Tr: 4.85l.
    • 37. 1-(5-(2-(1H-Tetrazol-5-yl)phenyl)-2-(cyclohexyl(methyl)amino)pyridin-3-yl)-3-(2-fluorophenyl)urea
  • Figure imgb0219
  • The title compound was prepared from 37C at 95 °C by the procedure used for the conversion of 8D to 8. MS(ES): m/z = 487 [M+H]+. HPLC Tr: 11.53d.
    • Example 38 1-(4-Bromo-2-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
  • Figure imgb0220
    • 38A. N4,N4-Diisobutyl-2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-3,4-diamine
  • Figure imgb0221
  • A mixture of toluene (Ratio: 2.250, Volume: 9 mL) and water (Ratio: 1.000, Volume: 4 mL) was degassed by purges with nitrogen (3x). 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (4B) (2 g, 6.02 mmol), 5-(2-bromophenyl)-2-trityl-2H-tetrazole (2.56 g, 5.47 mmol) and sodium carbonate (1.160 g, 10.94 mmol) were added, and the reaction mixture was purged with nitrogen. Pd(Ph3P)4 (0.632 g, 0.547 mmol) was added, the mixture was degassed (3x), and the reaction mixture was heated at 80 °C under a nitrogen atmosphere for 14h. The reaction was cooled to room temperature, and the resulting mixture was extracted with DCM (3x 60ml), washed with water and brine, dried over anhydrous Na2SO4. Purification by ISCO chromatography (gradient elution with ethyl acetate-hexanes) afforded N4,N4-diisobutyl-2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-3,4-diamine (2.37 g, 3.91 mmol, 71.4% yield) as white solid. MS(ES): m/z = 607 [M+H]+. HPLC Tr: 1.28k.
    • 38. 1-(4-Bromo-2-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
  • Figure imgb0222
  • A solution of N4,N4-diisobutyl-2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine (38A) (0.2 g, 0.330 mmol) in THF (1 mL) was treated with 4-bromo-2-fluoro-1-isocyanatobenzene (0.093 g, 0.428 mmol) and warmed to 55 °C. After 1h, the solution was treated with 0.3 mL of 4 M aq. HCl and stirred 3h at RT. This mixture was treated with ~0.3 mL of DMF and a few drops of EtOH to give a solution, and then it was chromatographed on silica gel (elution with 1:1 ether-hexanes, 1% HOAc, gradient of EtOH from 0% to 5%). Concentration of the appropriate fractions afforded 1-(4-bromo-2-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea (0.058 g, 27.3% yield) as a colorless foam. MS(ES): m/z = 580 [M+H]+. HPLC Tr: 13.18d.
    • Example 39 1-(5-Chloro-4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0223
    • 39A. 4-Bromo-2-chloro-N,N-diisobutyl-6-nitroaniline
  • Figure imgb0224
  • A stirred, cooled (0 °C) solution of 4-bromo-N,N-diisobutyl-2-nitroaniline (1A) (0.494 g, 1.5 mmol) in DMF (4 mL) was treated with N-chlorosuccinimide (0.220 g, 1.650 mmol). The orange solution was warmed to RT and stirred 15 min. LCMS indicates that LTN reaction has occurred. The reaction was warmed with a heat gun to ~60 °C for a few seconds then cooled to RT with stirring over 10 min. TLC indicates SM and one spot at lower Rf and one spot at higher Rf. The reaction was treated with an additional 150 mg. of NCS and re-warmed to 60 °C. The reaction was then stirred overnight at RT. The reaction was purified by prep. HPLC (Axia Luna 30 x 100 mm column, gradient elution with MeOH-water-TFA, four injections). Concentration of the appropriate fractions afforded 4-bromo-2-chloro-N,N-diisobutyl-6-nitroaniline (0.27 g, 47.0% yield) as an orange oil. MS(ES): m/z = 363 [M+H]+. HPLC Tr: 5.52l.
    • 39B. 1-(5-Bromo-3-chloro-2-(diisobutylamino)phenyl)-3-p-tolylurea
  • Figure imgb0225
  • The title compound was prepared from 39A using the procedures for the conversion of 1A into 1C. MS(ES): m/z = 468 [M+H]+. HPLC Tr: 5.49l.
    • 39. 1-(5-Chloro-4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
  • Figure imgb0226
  • The title compound was prepared from 39B using the procedures for the conversion of 8D to 8. MS(ES): m/z = 532 [M+H]+. HPLC Tr: 5.00l.
    • Example 40 3'-Chloro-4'-(diisobutylamino)-5'-(3-p-tolylureido)biphenyl-2-carboxylic acid
  • Figure imgb0227
  • The title compound was prepared from 39B and 2-carboxyphenylboronic acid by the procedure described for the conversion of 8D to 8. MS(ES): m/z = 508 [M+H]+. HPLC Tr: 13.34d.
    • Example 41 3'-Chloro-4'-(diisobutylamino)-5-fluoro-5'-(3-p-tolylureido)biphenyl-2-carboxylic acid
  • Figure imgb0228
  • The title compound was prepared from 39B and 2-borono-4-fluorobenzoic acid by the procedure described for the conversion of 8D to 8. MS(ES): m/z = 526 [M+H]+. HPLC Tr: 5.23l.
  • Using the methods described for the preparation of 27B and 29B, amines RNH2 and carboxylic acids R'CO2H are coupled to give amides which are further transformed by the action of LiAlH4 into secondary amines RNHCH2R' (lx, Table 2) useful as intermediates in the synthesis of compounds of the present invention. Table 2
    Amine Starting Materials Made by Hydride Reduction of Amides
    Figure imgb0229
    R R' Coupling method (M+H)+ Tr
    lxa
    Figure imgb0230
    Figure imgb0231
         		acid chloride 156 1.46o
    lxb
    Figure imgb0232
    Figure imgb0233
         		acid chloride used in subsequent step without purification or characterization
    lxc
    Figure imgb0234
    Figure imgb0235
         		acid chloride 142 1.22o
    lxd
    Figure imgb0236
    Figure imgb0237
         		acid chloride 1H NMR (400 MHz, DMSO-d6) δ ppm 2.89-2.98(m, 1 H); 2.41(t, 2H, J = 7.0 Hz); 1.20-1.72(m, 10H); 0.84(t, 3H, J = 7.4 Hz).
    lxe
    Figure imgb0238
    Figure imgb0239
         		acid chloride 196 1.24q
    1xf
    Figure imgb0240
    Figure imgb0241
         		Bop 224 1.36o
    lxg
    Figure imgb0242
    Figure imgb0243
         		acid chloride 170 0.60p
    lxq
    Figure imgb0244
    Figure imgb0245
         		acid chloride 144 0.98p
    lxr
    Figure imgb0246
    Figure imgb0247
         		acid chloride 160 0.80p
    lxs
    Figure imgb0248
    Figure imgb0249
         		Bop 210 0.81p
  • Additional secondary amines RNHCHR'R"(lx) useful as intermediates in the synthesis of compounds of the present invention may be prepared by the scheme below. Some Examples prepared by this method are shown in Table 3a. The Example below utilizing sodium cyanoborohydride as the reducing agent and acetic acid as a proton source is representative and not intended to be limiting. Additional proton sources could include any number of inorganic acids such as HCl or HBr and other organic acids. Other reducing agents utilized for this transformation include but are not limited to sodium triacetoxyborohydride and sodium borohydride.
    • Example lxi N-(2,2-Difluoroethyl)cyclohexanamine, HCl
  • Figure imgb0250
  • To a stirred solution of 2,2-difluoroethanamine (0.446 g, 5.50 mmol)in DMF (5 mL) and acetic acid (0.572 mL, 10.00 mmol) was added cyclohexanone (0.491 g, 5 mmol) followed by a solution of sodium cyanoborohydride (6.00 mL, 6.00 mmol) in THF. The solution was stirred overnight at RT. The reaction was diluted with ether and treated with 0.5M aq. HCl. The phases were stirred together for 1h, separated, and the aq. phase was brought to pH 10 with sat. aq. sodium carbonate. The resulting mixture was extracted with ether, and the organic extract was dried and concentrated to afford a colorless oil. This oil was dissolved in ether, treated with 2 mL of 4M HCl in dioxane, and the resulting solid was filtered, rinsed with ether, and air-dried to afford N-(2,2-difluoroethyl)cyclohexanamine, HCl (0.5 g, 47.6% yield) as a white powder. MS(ES): m/z = 164 [M+H]+. HPLC Tr: 0.55p.
  • Using the methods described for the preparation of lxi, amines RNH2 and aldehydes/ketones R'COR" are condensed to secondary amines RNHCHR'R" (lx, Table 3 a) useful as intermediates in the synthesis of compounds of the present invention. Table 3 a
    Amine Starting Materials Made by Reductive Amination
    Figure imgb0251
    Entry RNH2 R'COR" (M+H)+ Tr
    lxj
    Figure imgb0252
    Figure imgb0253
         		196 1.00p
    lxk
    Figure imgb0254
    Figure imgb0255
         		210 1.18p
    lxl
    Figure imgb0256
    Figure imgb0257
         		142 (Crude product was derivatized as the t-butyl carbamate for purification, then deprotected to give the desired amine·HCl.) 1.36p
  • Additional secondary amines RNHCHR'R"(lx) useful as intermediates in the synthesis of compounds of the present invention may be prepared by the scheme below. Some Examples prepared by this method are shown in Table 3b.
    • Example lxs 4,4,4-trifluoro-N-(2-methylallyl)butan-1-amine
  • Figure imgb0258
  • A solution of 4,4,4-trifluorobutanal (3.72 g, 29.5 mmol) and 2-methylprop-2-en-1-amine (2, 28.1 mmol) in MeOH (14.06 ml) was warmed to 40°C for 30 min. then cooled to RT. This solution was treated with sodium borohydride (1.596 g, 42.2 mmol) and stirred ON at RT. The reaction was diluted with water and extracted twice with ether. The comb. org. ext. dried and stripped to afford 4,4,4-trifluoro-N-(2-methylallyl)butan-1-amine (2.9 g, 14.40 mmol, 51.2 % yield) as a colorless oil. MS(ES): m/z = 182 [M+H]+. HPLC Tr: 0.53k.
  • Using the methods described for the preparation of lxs, amines RNH2 and aldehydes/ketones R'COR" are converted to secondary amines RNHCHR'R" (lx, Table 3b) useful as intermediates in the synthesis of compounds of the present invention. Table 3b
    Amine Starting Materials Made by Reductive Amination
    Figure imgb0259
    Entry RNH2 R'COR" (M+H)+ Tr
    lxt
    Figure imgb0260
    Figure imgb0261
         		200 1.12p
    lxu
    Figure imgb0262
    Figure imgb0263
         		228 1.02p
    lxv
    Figure imgb0264
    Figure imgb0265
         		200 0.49k
    lxw
    Figure imgb0266
    Figure imgb0267
         		226 (M-H)- 1.31w
    lxy
    Figure imgb0268
    Figure imgb0269
         		224 0.64s
  • Additional secondary amines RNHCHR'R" (lx, R" = H) useful as intermediates in the synthesis of compounds of the present invention may be prepared by carbamate N-alkylation followed by carbamate deprotection as shown in the scheme below. Some Examples prepared by this method are shown in Table 4. The Example below utilizing a t-butyl carbamate with sodium hydride as the base is representative and not intended to be limiting. Benzyl carbamates are also suitable groups for activating amines for alkylation and are removed under reducing conditions. Other bases of suitable strength include lithium dialkylamides and the related disilylazides and others known to those skilled in the art of organic/medicinal chemistry.
    • Example lxm N-(Cyclopropylmethyl)-2,2-difluoroethanamine, HCl
  • Figure imgb0270
    • lxm, Part A. tert-Butyl 2,2-difluoroethylcarbamate
  • Figure imgb0271
  • A solution of 2,2-difluoroethanamine (0.892 g, 11.00 mmol) in THF (Volume: 10 mL) was treated with di-tert-butyl dicarbonate (2.182 g, 10 mmol) followed by N-methylmorpholine (1.099 mL, 10.00 mmol). The solution was stirred 1.5h at RT then diluted with ether. This solution was washed with diluted aq. HOAc then aq. sodium bicarbonate, dried, and concentrated to afford tert-butyl 2,2-difluoroethylcarbamate (1.8 g, 94% yield) as a colorless crystalline solid. MS(ES): m/z = 182 [M+H]+. HPLC Tr: 2.241.
    • lxm, Part B. tert-Butyl cyclopropylmethyl(2,2-difluoroethyl)carbamate
  • Figure imgb0272
  • To a stirred solution of tert-butyl 2,2-difluoroethylcarbamate (0.544 g, 3 mmol) in DMF (Volume: 4 mL) was added sodium hydride (0.180 g, 4.50 mmol). The mixture was placed under nitrogen and stirred for 10 min. then treated with (bromomethyl)cyclopropane (0.567 g, 4.20 mmol). The reaction was stirred 1.5h at RT then quenched with diluted aq. HOAc. The resulting mixture was diluted with ether and washed with water then sat. aq. sodium bicarbonate. The organic phase was dried and concentrated to afford tert-butyl cyclopropylmethyl(2,2-difluoroethyl)carbamate (0.64 g, 86% yield) as a colorless oil. MS(ES): m/z = 180 [M+H - isobutylene]+. HPLC Tr: 1.85°.
    • lxm. N-(Cyclopropylmethyl)-2,2-difluoroethanamine, HCl
  • Figure imgb0273
  • tert-Butyl cyclopropylmethyl(2,2-difluoroethyl)carbamate (0.6 g, 2.55 mmol) was treated with a solution of HCl (2.55 ml, 10.20 mmol) in dioxane. The solution was stirred 1h at RT then concentrated under reduced pressure to afford an oily white solid. This material was suspended in 30% ether-hexanes and filtered, rinsed with 30% ether-hexanes, and air-dried to afford N-(cyclopropylmethyl)-2,2-difluoroethanamine, HCl (0.37 g, 80% yield) as a colorless solid. MS(ES): m/z = 180 [M+H]+. HPLC Tr: 0.28°.
  • Using the methods described for the preparation of lxm, amines RNH2 are derivatized as t-butyl carbamates, alkylated, and then deprotected to afford secondary amine hydrochloride salts RNHCH2R'·HCl (lx, Table 4) useful as intermediates in the synthesis of compounds of the present invention. Table 4
    Amine Starting Materials Made by Carbamate Alkylation
    Figure imgb0274
    RNH2 R'CH2X" (M+H)+ Tr
    lxn
    Figure imgb0275
    Figure imgb0276
         		142 0.99p
    lxo
    Figure imgb0277
    Figure imgb0278
         		1H NMR (400 MHz, DMSO-d6) δ ppm 0.84(br.s, 1 H); 2.91-3.0(m, 2H); 2.71-2.75(br.s, 2H); 1.26(t, 3H, J = 7.3 Hz); 1.01(s, 9H). 1.18p
    lxp
    Figure imgb0279
    Figure imgb0280
         		154 1.47l
  • Using the methods described for the conversion of 1B to 1C, aniline intermediates iii and the appropriate isocyanate R9NCO are converted to the urea intermediates iv (Table 5, Z = NR7R8). Table 5
    Bromourea Intermediates Made by Scheme 1
    Figure imgb0281
    R9 NR7R8 Temp. (°C) (M+H)+ Tr
    iva
    Figure imgb0282
    Figure imgb0283
         		60 418 4.58l
    ivb
    Figure imgb0284
    Figure imgb0285
         		60 438 4.51l
    ivd
    Figure imgb0286
    Figure imgb0287
         		50 444 5.05l
    ive
    Figure imgb0288
    Figure imgb0289
         		50 420 4.38l
    ivg
    Figure imgb0290
    Figure imgb0291
         		55 424 4.03l
    ivh
    Figure imgb0292
    Figure imgb0293
         		60 438 4.07l
    ivi
    Figure imgb0294
    Figure imgb0295
         		50 418 3.97l
    ivk
    Figure imgb0296
    Figure imgb0297
         		55 440 4.77l
    ivl
    Figure imgb0298
    Figure imgb0299
         		55 472 5.07l
    ivm
    Figure imgb0300
    Figure imgb0301
         		55 430 5.43l
    ivn
    Figure imgb0302
    Figure imgb0303
         		45 408 1.93o
    ivo
    Figure imgb0304
    Figure imgb0305
         		55 432 4.65l
    ivp
    Figure imgb0306
    Figure imgb0307
         		55 458 2.25o
    ivq
    Figure imgb0308
    Figure imgb0309
         		55 446 2.45p
    ivr
    Figure imgb0310
    Figure imgb0311
         		55 434 2.47p
    ivs
    Figure imgb0312
    Figure imgb0313
         		55 432 2.47p
    ivt
    Figure imgb0314
    Figure imgb0315
         		60 446 2.57p
    ivu
    Figure imgb0316
    Figure imgb0317
         		60 454 2.87p
    ivv
    Figure imgb0318
    Figure imgb0319
         		60 424 2.96p
    ivw
    Figure imgb0320
    Figure imgb0321
         		60 422 2.82p
    ivx
    Figure imgb0322
    Figure imgb0323
         		60 420 3.01p
    ivy
    Figure imgb0324
    Figure imgb0325
         		60 418 2.87p
    ivz
    Figure imgb0326
    Figure imgb0327
         		55 460 3.51q
    ivaa
    Figure imgb0328
    Figure imgb0329
         		55 464 3.43q
    ivac
    Figure imgb0330
    Figure imgb0331
         		55 446 3.43q
    ivad
    Figure imgb0332
    Figure imgb0333
         		55 450 3.38q
    ivae
    Figure imgb0334
    Figure imgb0335
         		55 456 3.42q
    ivag
    Figure imgb0336
    Figure imgb0337
         		60 420 3.31q
    ivah
    Figure imgb0338
    Figure imgb0339
         		60 424 3.23q
    ivai
    Figure imgb0340
    Figure imgb0341
         		60 442 3.27q
    ivaj
    Figure imgb0342
    Figure imgb0343
         		50 514 3.48q
    ival
    Figure imgb0344
    Figure imgb0345
         		55 418 4.56l
    ivam
    Figure imgb0346
    Figure imgb0347
         		45 432 3.25q
    ivan
    Figure imgb0348
    Figure imgb0349
         		45 434 3.21q
    ivao
    Figure imgb0350
    Figure imgb0351
         		45 428 3.20q
    ivap
    Figure imgb0352
    Figure imgb0353
         		45 446 2.89q
    ivaq
    Figure imgb0354
    Figure imgb0355
         		45 450 2.84q
    ivar
    Figure imgb0356
    Figure imgb0357
         		60 460 2.85q
    ivas
    Figure imgb0358
    Figure imgb0359
         		60 392 2.65q
    ivat
    Figure imgb0360
    Figure imgb0361
         		45 432 2.85q
    ivau
    Figure imgb0362
    Figure imgb0363
         		50 454 1.23k
    ivav
    Figure imgb0364
    Figure imgb0365
         		60 528 2.94q
    ivaw
    Figure imgb0366
    Figure imgb0367
         		50 502 3.25r
    ivax
    Figure imgb0368
    Figure imgb0369
         		45 504 2.80q
    ivay
    Figure imgb0370
    Figure imgb0371
         		45 468 2.79q
    ivaz
    Figure imgb0372
    Figure imgb0373
         		45 500 3.28r
    ivba
    Figure imgb0374
    Figure imgb0375
         		50 474 2.84q
    ivbb
    Figure imgb0376
    Figure imgb0377
         		45 506 2.86q
    ivbc
    Figure imgb0378
    Figure imgb0379
         		45 502 1.31k
    ivbd
    Figure imgb0380
    Figure imgb0381
         		45 454 3.21r
    ivbe
    Figure imgb0382
    Figure imgb0383
         		50 470 1.22k
    ivbf
    Figure imgb0384
    Figure imgb0385
         		50 468 3.18r
    ivbg
    Figure imgb0386
    Figure imgb0387
         		RT 484 5.16l
    ivbh
    Figure imgb0388
    Figure imgb0389
         		RT 532 5.04l
    ivbi
    Figure imgb0390
    Figure imgb0391
         		RT 504 5.04l
    ivbj
    Figure imgb0392
    Figure imgb0393
         		RT 504 1.23k
    ivbk
    Figure imgb0394
    Figure imgb0395
         		50 448 5.21l
    ivbl
    Figure imgb0396
    Figure imgb0397
         		50 486 5.39l
    ivbm
    Figure imgb0398
    Figure imgb0399
         		50 452 5.11l
    ivbn
    Figure imgb0400
    Figure imgb0401
         		50 462 4.97l
    ivbo
    Figure imgb0402
    Figure imgb0403
         		50 500 5.33l
    ivbp
    Figure imgb0404
    Figure imgb0405
         		RT 458 5.18l
    ivbq
    Figure imgb0406
    Figure imgb0407
         		RT 464 4.57l
    ivbr
    Figure imgb0408
    Figure imgb0409
         		RT 512 1.28k
    ivbs
    Figure imgb0410
    Figure imgb0411
         		55 528 5.35l
    ivbt
    Figure imgb0412
    Figure imgb0413
         		55 532 5.27l
  • Using the method described for the conversion of 2A to 2B, bromide intermediates viii and the appropriate arylboronic acid are converted to the biaryl intermediates x (Table 6, Z = NR7R8). Table 6
    Biaryldiamine Intermediates Made by Scheme 2
    Figure imgb0414
    Figure imgb0415
         		-NR7R8 (M+H)+ Tr
    va
    Figure imgb0416
    Figure imgb0417
         		391 3.93l
    vb
    Figure imgb0418
    Figure imgb0419
         		325 2.88l
    vc
    Figure imgb0420
    Figure imgb0421
         		363 2.59l
    vd
    Figure imgb0422
    Figure imgb0423
         		341 2.67q
  • Using the methods described for the conversion of 1B to 1C, aniline intermediates iii and the appropriate isocyanate R9NCO are converted to the urea intermediates iv. Table 7
    B5F Bromourea Intermediates Made by Scheme 1
    Figure imgb0424
    Ex. R9 -NR7R8 Temp. (°C) (M+H)+ Tr
    ivca
    Figure imgb0425
    Figure imgb0426
         		60 436 5.05l
    ivcb
    Figure imgb0427
    Figure imgb0428
         		55 4.58 4.22l
    ivcc
    Figure imgb0429
    Figure imgb0430
         		55 478 3.65q
    ivcd
    Figure imgb0431
    Figure imgb0432
         		45 482 3.60q
    ivce
    Figure imgb0433
    Figure imgb0434
         		45 500 3.65q
    ivcf
    Figure imgb0435
    Figure imgb0436
         		45 452 5.22l
    ivcg
    Figure imgb0437
    Figure imgb0438
         		45 490 5.39l
  • Using the method described for the conversion of 1B to 1C, aniline intermediates (iii) and the appropriate isocyanate R9NCO are converted to the urea intermediates (iv). Table 8
    Figure imgb0439
    Ex. R9 -NR7R8 Temp. (°C) (M+H)+ Tr
    ivda
    Figure imgb0440
    Figure imgb0441
         		50 482 5.49l
    ivdb
    Figure imgb0442
    Figure imgb0443
         		50 478 5.59l
    ivdc
    Figure imgb0444
    Figure imgb0445
         		50 516 5.75q
    • Examples 42 to 210
  • The following compounds of the invention set out in Table 9 were prepared employing the process set out below Table 9
    Figure imgb0446
    Ex. No. Name
    Figure imgb0447
         		R9 -NR7R8 Tr method (M+H) +
    42 3'-(3-(2-chlorophenyl)ureid o)-4'-(cyclohexyl(methyl )amino)-4-methoxybiphenyl-3-carboxylic acid
    Figure imgb0448
    Figure imgb0449
    Figure imgb0450
         		11.53b 508
    43 4'-(cyclohexyl(methyl )amino)-4-methoxy-3'-(3-p-tolylureido)bipheny 1-3-carboxylic acid
    Figure imgb0451
    Figure imgb0452
    Figure imgb0453
         		11.61b 488
    44 1-(4-(cyclohexyl(methyl )amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0454
    Figure imgb0455
    Figure imgb0456
         		11.77b 482
    45 1-(2-chlorophenyl)-3-(4-(cyclohexyl (methyl)amino)-2'-(1H-tetrazol-5-yl) biphenyl-3-yl)urea
    Figure imgb0457
    Figure imgb0458
    Figure imgb0459
         		11.67b 502
    46 1-(4-(cyclohexylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0460
    Figure imgb0461
    Figure imgb0462
         		11.76b 468
    47 1-(4-((4aS,8aS)-octahydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0463
    Figure imgb0464
    Figure imgb0465
         		13.09b 508
    48 4'-(cyclohexyl amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0466
    Figure imgb0467
    Figure imgb0468
         		11.16b 444
    49 4'-((4aS,8aS)-octahydroquinolin-1(2H)-yl)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0469
    Figure imgb0470
    Figure imgb0471
         		12.42b 484
    50 1-(4-(methyl(tetra hydro-2H-pyran-4-yl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0472
    Figure imgb0473
    Figure imgb0474
         		11.65b 484
    51 4'-(methyl(tetra hydro-2H-pyran-4-yl)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0475
    Figure imgb0476
    Figure imgb0477
         		11.54b 460
    52 4'-(diisobutyl amino)-3'-(3-p-tolylureido) biphenyl-2-carboxylic acid
    Figure imgb0478
    Figure imgb0479
    Figure imgb0480
         		13.35b 474
    53 1-(4-(cyclohexyl (ethyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl) urea
    Figure imgb0481
    Figure imgb0482
    Figure imgb0483
         		11.38b 500
    54 4'-((2,2-dimethoxyethyl)(m ethyl)amino)-3'-(3-p-tolylureido) biphenyl-2-carboxylic acid
    Figure imgb0484
    Figure imgb0485
    Figure imgb0486
         		11.99b 464
    55 1-(4-((2,2-dimethoxyethyl)(m ethyl) amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0487
    Figure imgb0488
    Figure imgb0489
         		11.95b 488
    56 4'-(bis(2-methoxyethyl)amin o)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0490
    Figure imgb0491
    Figure imgb0492
         		12.13b 478
    57 1-(4-(bis(2-methoxyethyl)amin o)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0493
    Figure imgb0494
         		12.01b 502
    58 4'-((cyclopropylmethy 1)(propyl)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0496
    Figure imgb0497
    Figure imgb0498
         		11.36d 458
    59 1-(4-((cyclopropylmethy 1)(propyl) amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0499
    Figure imgb0500
    Figure imgb0501
         		11.71b 482
    60 1-(4-((cyclopropylmethy 1)(2,2-difluoroethyl)amino )-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0502
    Figure imgb0503
    Figure imgb0504
         		16.81a 504
    61 4'-((cyclopropylmethy 1)(2,2-difluoroethyl)amino )-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0505
    Figure imgb0506
    Figure imgb0507
         		17.15a 480
    62 4'-((cyclopropylmethy 1)(2,2-difluoroethyl)amino )-4-methoxy-3'-(3-p-tolylureido)bipheny 1-3-carboxylic acid
    Figure imgb0508
    Figure imgb0509
    Figure imgb0510
         		17.05a 510
    63 1-(4-((cyclopropylmethy 1)(3,3,3-trifluoropropyl)ami no)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0511
    Figure imgb0512
    Figure imgb0513
         		12.86b 536
    64 4'-((cyclopropylmethy 1)(3,3,3-trifluoropropyl)ami no)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0514
    Figure imgb0515
    Figure imgb0516
         		17.66a 512
    65 4'-((cyclopropylmethy 1)(3,3,3-trifluoropropyl)ami no)-4-methoxy-3'-(3-p-tolylureido)bipheny 1-3-carboxylic acid
    Figure imgb0517
    Figure imgb0518
    Figure imgb0519
         		13.01b 542
    66 1-(4-(bis(cyclopropylmet hyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0520
    Figure imgb0521
    Figure imgb0522
         		15.24a 494
    67 4'-(bis(cyclopropylmet hyl)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0523
    Figure imgb0524
    Figure imgb0525
         		14.54a 470
    68 3'-(3-(2-chlorophenyl)ureid o)-4'-(diisobutylamino)-4-fluorobiphenyl-2-carboxylic acid
    Figure imgb0526
    Figure imgb0527
    Figure imgb0528
         		7.27m 512
    69 4'-(diisobutylamino)-3-fluoro-3'-(3-o-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0529
    Figure imgb0530
    Figure imgb0531
         		7.14m 492
    70 4'-(diisobutylamino)-4-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0532
    Figure imgb0533
    Figure imgb0534
         		7.10m 492
    71 N-(4'-(diisobutylamino)-4-methoxy-3'-(3-p-tolylureido)bipheny 1-2-yl)-1,1,1-trifluoromethanesul fonamide
    Figure imgb0535
    Figure imgb0536
    Figure imgb0537
         		7.94m 607
    72 4'-(ethyl(2-methoxyethyl)amin o)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0538
    Figure imgb0539
    Figure imgb0540
         		15.32a 448
    73 1-(4-(ethyl(2-methoxyethyl)amin o)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0541
    Figure imgb0542
    Figure imgb0543
         		15.79a 472
    74 N-(4'-(diisobutylamino)-3'-(3-p-tolylureido)bipheny 1-2-yl) methanesulfonamid e
    Figure imgb0544
    Figure imgb0545
    Figure imgb0546
         		7.01m 523
    75 1-(4-(cyclopentyl(ethyl)a mino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0547
    Figure imgb0548
    Figure imgb0549
         		15.60a 482
    76 4'-(cyclopentyl(ethyl)a mino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0550
    Figure imgb0551
    Figure imgb0552
         		14.90a 458
    77 4'-(cyclopentyl(ethyl)a mino)-4-methoxy-3'-(3-p-tolylureido)bipheny 1-3-carboxylic acid
    Figure imgb0553
    Figure imgb0554
    Figure imgb0555
         		13.56a 488
    78 4'-(cycloheptyl(methyl )amino)-4-methoxy-3'-(3-p-tolylureido)bipheny 1-3-carboxylic acid
    Figure imgb0556
    Figure imgb0557
    Figure imgb0558
         		16.00a 502
    79 1-(4-(cycloheptyl(methyl )amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0559
    Figure imgb0560
    Figure imgb0561
         		16.29a 496
    80 4'-(cycloheptyl(methyl )amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0562
    Figure imgb0563
    Figure imgb0564
         		15.42a 472
    81 N-(4'-(diisobutylamino)-4-fluoro-3'-(3-p-tolylureido)bipheny 1-2-yl)-1,1,1-trifluoromethanesul fonamide
    Figure imgb0565
    Figure imgb0566
    Figure imgb0567
         		8.32m 595
    82 1-(4-(cyclohexyl(cyclopr opylmethyl) amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0568
    Figure imgb0569
    Figure imgb0570
         		16.55a 522
    83 4'-(cyclohexyl(cyclopr opylmethyl) amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0571
    Figure imgb0572
    Figure imgb0573
         		15.81a 498
    84 N-(4'-(diisobutylamino)-3'-(3-p-tolylureido)bipheny 1-2-yl)-2,2,2-trifluoroethanesulfo namide
    Figure imgb0574
    Figure imgb0575
    Figure imgb0576
         		7.67m 591
    85 1-(4-(cyclohexyl(propyl) amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0577
    Figure imgb0578
    Figure imgb0579
         		16.81a 510
    86 4'-(cyclohexyl(propyl) amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0580
    Figure imgb0581
    Figure imgb0582
         		16.09a 486
    87 4'-(cyclohexyl(propyl) amino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0583
    Figure imgb0584
    Figure imgb0585
         		17.11a 504
    88 1-(4-(dibutylamino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0586
    Figure imgb0587
    Figure imgb0588
         		12.48b 498
    89 4'-(dibutylamino)-3'-(3-p-tolylureido) biphenyl-2-carboxylic acid
    Figure imgb0589
    Figure imgb0590
    Figure imgb0591
         		16.27a 474
    90 4'-(dibutylamino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0592
    Figure imgb0593
    Figure imgb0594
         		17.28a 492
    91 2-(4-(dibutylamino)-3-(3-p-tolylureido) phenyl)thiophene-3-carboxylic acid
    Figure imgb0595
    Figure imgb0596
    Figure imgb0597
         		17.46a 480
    92 1-(4-((cyclopropylmethy 1)(isobutyl) amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0598
    Figure imgb0599
    Figure imgb0600
         		1.90k 496
    93 4'-((cyclopropylmethy 1)(isobutyl)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0601
    Figure imgb0602
    Figure imgb0603
         		1.87k 472
    96 1-(2'-(2-cyano-2-(methylsulfonyl) acetyl)-4-(diisobutylamino)bi phenyl-3-yl)-3-p-tolylurea
    Figure imgb0604
    Figure imgb0605
    Figure imgb0606
         		5.50m 575
    97 4'-((cyclobutylmethyl) (isobutyl)amino)-3'-(3-p-tolylureido)bipheny 1-3-carboxylic acid
    Figure imgb0607
    Figure imgb0608
    Figure imgb0609
         		1.57k 486
    98 1-(4-((cyclobutylmethyl) (isobutyl) amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0610
    Figure imgb0611
    Figure imgb0612
         		2.79i 510
    99 4'-((cyclobutylmethyl) (isobutyl)amino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0613
    Figure imgb0614
    Figure imgb0615
         		2.86i 504
    100 4'-((cyclobutylmethyl) (isobutyl)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0616
    Figure imgb0617
    Figure imgb0618
         		1.59k 486
    101 4'-(diisobutylamino)-6-(dimethylamino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0619
    Figure imgb0620
    Figure imgb0621
         		2.29j 517
    102 4-(4-(diisobutylamino)-3-(3-p-tolylureido)phenyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid
    Figure imgb0622
    Figure imgb0623
    Figure imgb0624
         		1.95k 506
    103 5-(4-(diisobutylamino)-3-(3-p-tolylureido)phenyl)t hiazole-4-carboxylic acid
    Figure imgb0625
    Figure imgb0626
    Figure imgb0627
         		2.05k 481
    104 4'-((4,4-difluorocyclohexyl) (methyl) amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0628
    Figure imgb0629
    Figure imgb0630
         		16.82a 494
    105 4'-((4,4-difluorocyclohexyl) (methyl) amino)-5-fluoro-3'-(3-p-tolylureido) biphenyl-2-carboxylic acid
    Figure imgb0631
    Figure imgb0632
    Figure imgb0633
         		17.35a 512
    106 1-(4-((4,4-difluorocyclohexyl) (methyl) amino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0634
    Figure imgb0635
    Figure imgb0636
         		16.74a 518
    107 4'-(2-ethylpiperidin-1-yl)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0637
    Figure imgb0638
    Figure imgb0639
         		1.76k 458
    108 4'-(ethyl(neopentyl)a mino)-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0640
    Figure imgb0641
    Figure imgb0642
         		1.95k 464
    109 1-(4-(2-ethylpiperidin-1-yl)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0643
    Figure imgb0644
    Figure imgb0645
         		1.63k 486
    110 1-(4-(ethyl(neopentyl)a mino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0646
    Figure imgb0647
    Figure imgb0648
         		2.10k 484
    111 4'-(ethyl(neopentyl)a mino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0649
    Figure imgb0650
    Figure imgb0651
         		2.04k 460
    112 1-(4-(ethyl(neopentyl)a mino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0652
    Figure imgb0653
    Figure imgb0654
         		2.01k 488
    113 4'-(ethyl(neopentyl)a mino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0655
    Figure imgb0656
    Figure imgb0657
         		2.16k 478
    114 1-(4-(2-ethylpiperidin-1-yl)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0658
    Figure imgb0659
    Figure imgb0660
         		1.75k 482
    115 4'-(ethyl(neopentyl)a mino)-5-fluoro-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0661
    Figure imgb0662
    Figure imgb0663
         		2.09k 482
    116 4'-(2-ethylpiperidin-1-yl)-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0664
    Figure imgb0665
    Figure imgb0666
         		1.64k 462
    117 1-(4-(diisobutylamino)-4'-methoxy-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0667
    Figure imgb0668
    Figure imgb0669
         		7.23m 528
    118 1-(4-(cyclohexyl(isobuty 1)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0670
    Figure imgb0671
    Figure imgb0672
         		18.20a 524
    119 4'-(cyclohexyl(isobuty 1)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0673
    Figure imgb0674
    Figure imgb0675
         		17.91a 500
    120 4-chloro-4'-(cyclohexyl(isobuty 1)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0676
    Figure imgb0677
    Figure imgb0678
         		19.73a 534
    121 1-(4-(cyclohexyl(isobuty 1)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0679
    Figure imgb0680
    Figure imgb0681
         		17.79a 528
    122 4'-(cyclohexyl(isobuty 1)amino)-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0682
    Figure imgb0683
    Figure imgb0684
         		17.53a 504
    123 4-chloro-4'-(cyclohexyl(isobuty 1)amino)-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0685
    Figure imgb0686
    Figure imgb0687
         		19.11a 538
    124 4'-(cyclohexyl(isobuty 1)amino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0688
    Figure imgb0689
    Figure imgb0690
         		2.26k 518
    125 4'-(cyclohexyl(isobuty 1)amino)-5-fluoro-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0691
    Figure imgb0692
    Figure imgb0693
         		2.18k 522
    126 4'-(diisobutylamino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0694
    Figure imgb0695
    Figure imgb0696
         		2.28k 492
    127 4-chloro-4'-(diisobutylamino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0697
    Figure imgb0698
    Figure imgb0699
         		2.36k 508
    128 4'-(diisobutylamino)-5-methoxy-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0700
    Figure imgb0701
    Figure imgb0702
         		17.91a 504
    129 1-(4-((2-cyclopropylethyl)(is obutyl) amino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0703
    Figure imgb0704
    Figure imgb0705
         		17.77a 510
    130 4'-((2-cyclopropylethyl)(is obutyl) amino)-5-fluoro-3'-(3-p-tolylureido) biphenyl-2-carboxylic acid
    Figure imgb0706
    Figure imgb0707
    Figure imgb0708
         		18.33a 504
    131 2-(4-((2-cyclopropylethyl)(is obutyl)amino)-3-(3-p-tolylureido)phenyl) thiophene-3-carboxylic acid
    Figure imgb0709
    Figure imgb0710
    Figure imgb0711
         		18.32a 492
    132 4'-((2-cyclopropylethyl)(is obutyl)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0712
    Figure imgb0713
    Figure imgb0714
         		17.50a 486
    133 1-(4-((2-cyclopropylethyl)(is obutyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0715
    Figure imgb0716
    Figure imgb0717
         		2.10k 514
    134 4'-((2-cyclopropylethyl)(is obutyl)amino)-3'-(3-(2-fluorophenyl)ureido ) biphenyl-2-carboxylic acid
    Figure imgb0718
    Figure imgb0719
    Figure imgb0720
         		2.05k 490
    135 4'-((2-cyclopropylethyl)(is obutyl)amino)-5-fluoro-3'-(3-(2-fluorophenyl) ureido)biphenyl-2-carboxylic acid
    Figure imgb0721
    Figure imgb0722
    Figure imgb0723
         		2.18k 508
    136 2-(4-((2-cyclopropylethyl)(is obutyl)amino)-3-(3-(2-fluorophenyl)ureido ) phenyl)thiophene-3-carboxylic acid
    Figure imgb0724
    Figure imgb0725
    Figure imgb0726
         		2.22k 496
    137 1-(2,4-difluorophenyl)-3-(4-(diisobutylamino)-2'-(lH-tetrazol-5-yl) biphenyl-3-yl)urea
    Figure imgb0727
    Figure imgb0728
    Figure imgb0729
         		13.23b 520
    138 3'-(3-(2,4-difluorophenyl)urei do)-4'-(diisobutylamino)bi phenyl-2-carboxylic acid
    Figure imgb0730
    Figure imgb0731
    Figure imgb0732
         		13.21b 496
    139 1-cyclopropyl-3-(4-(diisobutylamino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb0733
    Figure imgb0734
    Figure imgb0735
         		2.16i 448
    140 1-cyclohexyl-3-(4-(diisobutylamino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb0736
    Figure imgb0737
    Figure imgb0738
         		2.59i 490
    141 1-(4-(diisobutylamino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)-3-neopentylurea
    Figure imgb0739
    Figure imgb0740
    Figure imgb0741
         		2.51i 478
    142 1-(cyclopropylmethyl )-3-(4-(diisobutylamino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb0742
    Figure imgb0743
    Figure imgb0744
         		2.29i 462
    143 1-(benzo[d]thiazol-6-yl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb0745
    Figure imgb0746
    Figure imgb0747
         		2.26i 541
    144 methyl 2-(3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)ureido) thiazole-5-carboxylate
    Figure imgb0748
    Figure imgb0749
    Figure imgb0750
         		2.26i 549
    145 1-(4-(diisobutylamino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)-3-(1,3,4-thiadiazol-2-yl)urea
    Figure imgb0751
    Figure imgb0752
    Figure imgb0753
         		1.91i 492
    146 3'-(3-(2,4-difluorophenyl)urei do)-4'-(diisobutylamino)-5-fluorobiphenyl-2-carboxylic acid
    Figure imgb0754
    Figure imgb0755
    Figure imgb0756
         		13.84b 514
    147 1-(4-(isobutyl(isopropyl) amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0757
    Figure imgb0758
    Figure imgb0759
         		12.68b 484
    148 4'-(isobutyl(isopropyl) amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0760
    Figure imgb0761
    Figure imgb0762
         		12.28b 460
    149 5-fluoro-4'-(isobutyl(isopropyl) amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0763
    Figure imgb0764
    Figure imgb0765
         		12.99b 478
    150 4'-(diisobutylamino)-3-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0766
    Figure imgb0767
    Figure imgb0768
         		2.06j 492
    151 3-(4-(diisobutylamino)-3-(3-p-tolylureido)phenyl)i sonicotinic acid
    Figure imgb0769
    Figure imgb0770
    Figure imgb0771
         		1.89k 475
    152 3-(4-(diisobutylamino)-3-(3-p-tolylureido)phenyl)f uran-2-carboxylic acid
    Figure imgb0772
    Figure imgb0773
    Figure imgb0774
         		2.70k 464
    153 1-(2-fluorophenyl)-3-(4-(isobutyl (isopropyl)amino)-2'-(lH-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb0775
    Figure imgb0776
    Figure imgb0777
         		1.97k 488
    154 3'-(3-(2-fluorophenyl)ureido )-4'-(isobutyl(isopropyl) amino)biphenyl-2-carboxylic acid
    Figure imgb0778
    Figure imgb0779
    Figure imgb0780
         		1.93k 464
    155 5-fluoro-3'-(3-(2-fluorophenyl)ureido )-4'-(isobutyl(isopropyl) amino)biphenyl-2-carboxylic acid
    Figure imgb0781
    Figure imgb0782
    Figure imgb0783
         		2.06k 482
    156 1-(2,4-difluorophenyl)-3-(4-(isobutyl (isopropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb0784
    Figure imgb0785
    Figure imgb0786
         		2.02k 506
    157 3'-(3-(2,4-difluorophenyl)urei do)-4'-(isobutyl(isopropyl) amino)biphenyl-2-carboxylic acid
    Figure imgb0787
    Figure imgb0788
    Figure imgb0789
         		1.98k 482
    158 3'-(3-(2,4-difluorophenyl)urei do)-5-fluoro-4'-(isobutyl(isopropyl) amino) biphenyl-2-carboxylic acid
    Figure imgb0790
    Figure imgb0791
    Figure imgb0792
         		2.09k 500
    159 4-(4-(diisobutylamino)-3-(3-p-tolylureido)phenyl) nicotinic acid
    Figure imgb0793
    Figure imgb0794
    Figure imgb0795
         		2.00k 475
    160 3'-(3-(2,4-difluorophenyl)urei do)-4'-(diisobutylamino)-5-methoxybiphenyl-2-carboxylic acid
    Figure imgb0796
    Figure imgb0797
    Figure imgb0798
         		2.28k 526
    161 1-(4-(cyclohexyl(isobuty 1)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-(trifluoromethyl)ph enyl)urea
    Figure imgb0799
    Figure imgb0800
    Figure imgb0801
         		2.37k 578
    162 4'-(cyclohexyl(isobuty 1)amino)-3'-(3-(2-(trifluoromethyl)ph enyl)ureido)biphen yl-2-carboxylic acid
    Figure imgb0802
    Figure imgb0803
    Figure imgb0804
         		2.38k 554
    163 4'-(cyclohexyl(isobuty 1)amino)-5-fluoro-3'-(3-(2-(trifluoromethyl)ph enyl)ureido) biphenyl-2-carboxylic acid
    Figure imgb0805
    Figure imgb0806
    Figure imgb0807
         		2.49k 572
    164 1-(5-(2-(1H-tetrazol-5-yl)cyclopent-1-enyl)-2-(diisobutylamino)p henyl)-3-p-tolylurea
    Figure imgb0808
    Figure imgb0809
    Figure imgb0810
         		2.21k 488
    165 4'-(cyclopentyl(propyl )amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0811
    Figure imgb0812
    Figure imgb0813
         		2.85q 472
    166 4'-(cyclopentyl(propyl )amino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0814
    Figure imgb0815
    Figure imgb0816
         		2.95q 490
    167 4'-(cyclopentyl(propyl )amino)-5-fluoro-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0817
    Figure imgb0818
    Figure imgb0819
         		1.77k 494
    168 4'-(cyclopentyl(propyl )amino)-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0820
    Figure imgb0821
    Figure imgb0822
         		2.75q 476
    169 1-(4-(cyclopentyl(propyl )amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0823
    Figure imgb0824
    Figure imgb0825
         		2.87q 496
    170 1-(4-(cyclopentyl(propyl )amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0826
    Figure imgb0827
    Figure imgb0828
         		2.76q 500
    171 4'-(cyclopentyl(isobut yl)amino)-5-fluoro-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0829
    Figure imgb0830
    Figure imgb0831
         		2.04k 504
    172 4'-(cyclopentyl(isobut yl)amino)-3'-(3-p-tolylureido)bipheny 1-2-carboxylic acid
    Figure imgb0832
    Figure imgb0833
    Figure imgb0834
         		2.41q 486
    173 4'-(cyclopentyl(isobut yl)amino)-3'-(3-(2-fluorophenyl)ureido )biphenyl-2-carboxylic acid
    Figure imgb0835
    Figure imgb0836
    Figure imgb0837
         		1.85k 490
    174 1-(4-(cyclopentyl(isobut yl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0838
    Figure imgb0839
    Figure imgb0840
         		2.47q 510
    175 1-(4-(cyclopentyl(isobut yl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0841
    Figure imgb0842
    Figure imgb0843
         		1.91k 514
    176 4'-(cyclopentyl(isobut yl)amino)-5-fluoro-3'-(3-(2-fluorophenyl)ureido ) biphenyl-2-carboxylic acid
    Figure imgb0844
    Figure imgb0845
    Figure imgb0846
         		2.47q 508
    177 4'-(butyl(cyclohexyl)a mino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0847
    Figure imgb0848
    Figure imgb0849
         		4.21l 500
    178 4'-(butyl(cyclohexyl)a mino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0850
    Figure imgb0851
    Figure imgb0852
         		4.41l 518
    179 1-(4-(isobutyl(methyl)a mino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0853
    Figure imgb0854
    Figure imgb0855
         		2.21q 456
    180 4'-(isobutyl(methyl)a mino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0856
    Figure imgb0857
    Figure imgb0858
         		2.17q 432
    181 5-fluoro-4'-(isobutyl(methyl)a mino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0859
    Figure imgb0860
    Figure imgb0861
         		2.31q 450
    182 4'-(cyclobutyl(isobutyl )amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0862
    Figure imgb0863
    Figure imgb0864
         		2.55q 490
    183 4'-(cyclobutyl(isobutyl )amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0865
    Figure imgb0866
    Figure imgb0867
         		2.41q 472
    184 1-(4-(cyclobutyl(isobutyl )amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0868
    Figure imgb0869
    Figure imgb0870
         		2.49q 496
    185 1-(4-(benzyl(propyl)ami no)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0871
    Figure imgb0872
    Figure imgb0873
         		2.52q 518
    186 4'-(benzyl(propyl)ami no)-5-ffuoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0874
    Figure imgb0875
    Figure imgb0876
         		2.56q 512
    187 4'-(benzyl(propyl)ami no)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0877
    Figure imgb0878
    Figure imgb0879
         		2.43q 494
    188 4'-(cyclohexyl(4,4,4-trifluoro-3-methylbutyl)amino) -3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0880
    Figure imgb0881
    Figure imgb0882
         		2.66q 568
    189 4'-(cyclohexyl(4,4,4-trifluoro-3-methylbutyl)amino) -5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0883
    Figure imgb0884
    Figure imgb0885
         		2.75q 586
    190 1-(4-(cyclohexyl(4,4,4-trifluoro-3-methylbutyl)amino) -2'-(lH-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0886
    Figure imgb0887
    Figure imgb0888
         		3.01r 592
    191 1-(4-((4-chlorobenzyl)(2-methoxyethyl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0889
    Figure imgb0890
    Figure imgb0891
         		2.62q 568
    192 4'-((4-chlorobenzyl)(2-methoxyethyl) amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0892
    Figure imgb0893
    Figure imgb0894
         		2.64q 544
    193 4'-((4-chlorobenzyl)(2-methoxyethyl) amino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0895
    Figure imgb0896
    Figure imgb0897
         		2.72q 562
    194 1-(4-(cyclohexyl(2,2-difluoroethyl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0898
    Figure imgb0899
    Figure imgb0900
         		2.60q 532
    195 1-(4-(cyclohexyl(3,3,3-trifluoropropyl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0901
    Figure imgb0902
    Figure imgb0903
         		2.96r 564
    196 4'-(cyclohexyl(2,2-difluoroethyl)amino )-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0904
    Figure imgb0905
    Figure imgb0906
         		2.66q 508
    197 4'-(cyclohexyl(3,3,3-trifluoropropyl) amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0907
    Figure imgb0908
    Figure imgb0909
         		2.75q 540
    198 4'-(isobutyl(3,3,3-trifluoropropyl) amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0910
    Figure imgb0911
    Figure imgb0912
         		2.90r 514
    199 1-(4-(isobutyl(3,3,3-trifluoropropyl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0913
    Figure imgb0914
    Figure imgb0915
         		2.23k 538
    200 5-fluoro-4'-(isobutyl(3,3,3-trifluoropropyl)ami no)-3'-(3-(p-tolyl) ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0916
    Figure imgb0917
    Figure imgb0918
         		2.99r 532
    201 1-(2-fluorophenyl)-3-(4-(isobutyl(4,4,4-trifluoro-3-methylbutyl)amino) -2'-(lH-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb0919
    Figure imgb0920
    Figure imgb0921
         		2.63q 570
    202 1-(4-(isobutyl(4,4,4-trifluoro-3-methylbutyl)amino) -2'-(lH-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0922
    Figure imgb0923
    Figure imgb0924
         		2.66q 566
    203 5-fluoro-4'-(isobutyl(4,4,4-trifluoro-3-methylbutyl)amino) -3'-(3-(p-tolyl) ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0925
    Figure imgb0926
    Figure imgb0927
         		2.74q 560
    204 5-fluoro-3'-(3-(2-fluorophenyl)ureido )-4'-(isobutyl(4,4,4-trifluoro-3-methylbutyl)amino) -[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0928
    Figure imgb0929
    Figure imgb0930
         		2.71q 564
    205 4'-(isobutyl(4,4,4-trifluoro-3-methylbutyl)amino) -3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0931
    Figure imgb0932
    Figure imgb0933
         		2.66q 542
    206 4'-((2-(tert-butyl)phenyl)amino )-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb0934
    Figure imgb0935
    Figure imgb0936
         		2.34k 494
    207 1-(4-((2-(tert-butyl)phenyl)(meth yl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0937
    Figure imgb0938
    Figure imgb0939
         		471l 536
    208 1-(4-((2-(tert-butyl)phenyl)amino )-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0940
    Figure imgb0941
    Figure imgb0942
         		2.27k 518
    209 4'-((2-(tert-butyl)phenyl)(meth yl)amino)-3'-(3-(2-fluorophenyl)ureido )-4-methoxy-[1,1'-biphenyl]-3-carboxylic acid
    Figure imgb0943
    Figure imgb0944
    Figure imgb0945
         		2.68q 542
    210 1-(4-((2-(tert-butyl)phenyl)(meth yl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb0946
    Figure imgb0947
    Figure imgb0948
         		2.69q 532
    • Examples 211 to 219
  • Using the methods described herein (the preparation of Example 2 from 2A is representative), the following compounds of the invention were prepared from aniline intermediates (v) and the appropriate isocyanates R9NCO. Table 10
    Figure imgb0949
    Ex. No. Name
    Figure imgb0950
         		R9 -NR7R8 Trmethod (M+H) +
    211 1-(4-(cyclohexyl(methyl)amino )-2'-(1H-tetrazol-5-yl) biphenyl-3-yl)-3-m-tolylurea
    Figure imgb0951
    Figure imgb0952
    Figure imgb0953
         		11.83b 482
    212 1-(4-(cyclohexyl(methyl)amino )-2'-(1H-tetrazol-5-yl) biphenyl-3-yl)-3-(2-(trifluoromethyl)phenyl)ur ea
    Figure imgb0954
    Figure imgb0955
    Figure imgb0956
         		11.69b 536
    213 4'-(cyclohexyl(methyl)amino )-3'-(3-p-tolylureido)biphenyl-2-carboxylic acid
    Figure imgb0957
    Figure imgb0958
    Figure imgb0959
         		11.14b 458
    214 1-(4-(cyclohexyl(methyl)amino )-2'-(1H-tetrazol-5-yl) biphenyl-3-yl)-3-(2-fluorophenyl)urea
    Figure imgb0960
    Figure imgb0961
    Figure imgb0962
         		11.47b 486
    215 3'-(3-(2-chlorophenyl)ureido)-4'-(cyclohexyl(methyl)amino ) biphenyl-2-carboxylic acid
    Figure imgb0963
    Figure imgb0964
    Figure imgb0965
         		3.661 478
    216 1-(4-(cyclohexyl(ethyl)amino)-2'-(1H-tetrazol-5-yl) biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0966
    Figure imgb0967
    Figure imgb0968
         		11.75b 496
    218 4'-(cyclohexyl(methyl)amino )-3'-(3-phenylureido)biphenyl-2-carboxylic acid
    Figure imgb0969
    Figure imgb0970
    Figure imgb0971
         		10.78b 444
    219 4'-(cyclohexyl(methyl)amino )-3'-(3-(2-fluorophenyl)ureido) biphenyl-2-carboxylic acid
    Figure imgb0972
    Figure imgb0973
    Figure imgb0974
         		10.90b 462
    • Examples 220 to 231
  • Using the methods described below, the following compounds of the invention were prepared. Table 11
    Figure imgb0975
    Ex. No. Name
    Figure imgb0976
         		R9 -NR7R8 HPLC Tr (M+H)+
    220 4'-(cyclohexyl(methyl)ami no)-2'-fluoro-4-methoxy-5'-(3-p-tolylureido)biphenyl-3-carboxylic acid
    Figure imgb0977
    Figure imgb0978
    Figure imgb0979
         		13.05b 506
    221 4'-(cyclohexyl(methyl)ami no)-2'-fluoro-5'-(3-p-tolylureido)biphenyl-2-carboxylic acid
    Figure imgb0980
    Figure imgb0981
    Figure imgb0982
         		12.49b 476
    222 1-(4-(cyclohexyl(methyl)ami no)-6-fluoro-2'-(1H-tetrazol-5-yl)biphenyl-3 - yl)-3-p-tolylurea
    Figure imgb0983
    Figure imgb0984
    Figure imgb0985
         		12.59b 500
    223 1-(4-((cyclopropylmethyl)(2, 2-difluoroethyl)amino)-6-fluoro-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3 -p-tolylurea
    Figure imgb0986
    Figure imgb0987
    Figure imgb0988
         		12.26b 522
    224 4'-((cyclopropylmethyl)(2, 2-difluoroethyl)amino)-2'-fluoro-5'-(3-p-tolylureido)biphenyl-2-carboxylic acid
    Figure imgb0989
    Figure imgb0990
    Figure imgb0991
         		12.47b 498
    225 4'-(cyclohexyl(isobutyl)ami no)-2'-fluoro-5'-(3-p-tolylureido)biphenyl-2-carboxylic acid
    Figure imgb0992
    Figure imgb0993
    Figure imgb0994
         		13.94b 518
    226 4'-(cyclohexyl(isobutyl)ami no)-5'-(3-(2,4-difluorophenyl)ureido)-2',5-difluoro-[1,1'-biphenyl] -2-carboxylic acid
    Figure imgb0995
    Figure imgb0996
    Figure imgb0997
         		3.30q 558
    227 1-(4-(cyclohexyl(isobutyl)ami no)-6-fluoro-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-p-tolylurea
    Figure imgb0998
    Figure imgb0999
    Figure imgb1000
         		3.22q 542
    228 4'-(cyclohexyl(isobutyl)ami no)-2'-fluoro-5'-(3-(2-fluorophenyl)ureido) biphenyl-2-carboxylic acid
    Figure imgb1001
    Figure imgb1002
    Figure imgb1003
         		3.16q 522
    229 4'-(cyclohexyl(isobutyl)ami no)-2',5-difluoro-5'-(3-(2-fluorophenyl)ureido) biphenyl-2-carboxylic acid
    Figure imgb1004
    Figure imgb1005
    Figure imgb1006
         		3.26q 540
    230 4'-(cyclohexyl(isobutyl)ami no)-5'-(3-(2,4-difluorophenyl)ureido)-2'-fluorobiphenyl-2-carboxylic acid
    Figure imgb1007
    Figure imgb1008
    Figure imgb1009
         		3.21q 540
    231 4'-(cyclohexyl(isobutyl)ami no)-2',5-difluoro-5'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb1010
    Figure imgb1011
    Figure imgb1012
         		3.32q 536
    • Example 232 4'-(Diisobutylamino)-N-(methylsulfonyl)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxamide
  • Figure imgb1013
  • To a solution of 4'-(diisobutylamino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid (Example 52) (40 mg, 0.084 mmol) in DMF (1 mL) was added DMAP (77 mg, 0.633 mmol), then EDC (162 mg, 0.845 mmol) and methanesulfonamide (121 mg, 1.267 mmol). The mixture was stirred at room temperature for 18h, filtered and purified by HPLC PHENOMENEX® Axia (Luna 5µ 30X100mm) 35% B (Solvent B = 90% MeOH - 10% H2O - 0.1% TFA) to 100% B in A (Solvent A = 10% MeOH - 90% H2O - 0.1% TFA) in 20 minutes and concentrated to obtain the product 4'-(diisobutylamino)-N-(methylsulfonyl)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxamide (19.4 mg, 0.035 mmol, 41.7% yield) LC/MS, m/z = 551.5(M+1). HPLC Rt = 1.04 min. LC/MS (BEH C18 2.1X 50mm, 1.7u, 0 to 100 B in 1 min with 0.5 min hold time, Flow rate = 1 ml/min, detection at 254 nm, Solvent A: 100% water / 0.1% TFA; Solvent B: 100% ACN / 0.1% TFA). 1H NMR (500MHz, methanol-d4) δ 8.05 (d, J=2.0 Hz, 1H), 7.59 - 7.46 (m, 3H), 7.44 - 7.36 (m, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.11 (d, J=7.9 Hz, 2H), 7.08 - 7.01 (m, 1H), 3.10 (s, 3H), 2.68 (d, J=6.9 Hz, 4H), 2.31 (s, 3H), 1.85 - 1.56 (m, 2H), 0.87 (d, J=6.4 Hz, 12H).
  • Following the procedure of Example 232, the following compounds were prepared.
    Figure imgb1014
    Example No. R [M+H]+ HPLC RT
    233
    Figure imgb1015
         		577.5 1.06v
    234
    Figure imgb1016
         		605.5 1.04v
    • Example 235 1-(4-(3,5-Dimethylpiperidin-1-yl)-2'-(1H-tetrazol-5-yl)-[[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1017
    • 235A. 1-(4-Bromo-2-nitrophenyl)-3,5-dimethylpiperidine
  • Figure imgb1018
  • A mixture of 4-bromo-1-fluoro-2-nitrobenzene (4 g, 18.18 mmol) and 3,5-dimethylpiperidine (2.058 g, 18.18 mmol) was heated at 130 °C for 3h, cooled to rt, diluted with DCM (5ml) and purified by Column chromatography (0-20% EtOAc/hexane; 220g column) to obtain 1-(4-bromo-2-nitrophenyl)-3,5-dimethylpiperidine (5.03 g, 16.06 mmol, 88% yield) as an orange oil. LC/MS, m/z = 314.4(M+1). HPLC Rt = 1.26 min. LC/MS (BEH C18 2.1X 50mm, 1.7u, 0 to 100 B in 1 min with 0.5 min hold time, Flow rate = 1 ml/min, detection at 254 nm, Solvent A: 100% water / 0.1% TFA; Solvent B: 100% ACN/ 0.1% TFA).
    • 235B. 5-Bromo-2-(3,5-dimethylpiperidin-1-yl)aniline
  • Figure imgb1019
  • 1-(4-Bromo-2-nitrophenyl)-3,5-dimethylpiperidine (235A) (6 g, 19.16 mmol) was taken up in EtOH (Ratio: 10.00, Volume: 60 mL) and water (Ratio: 1.000, Volume: 6 mL), zinc (12.53 g, 192 mmol) and ammonium chloride (10.25 g, 192 mmol) were added. The resulting exothermic reaction was stirred at room temperature for 30 minutes. The resulting solution turned to clear from orange color, was cooled at room temperature and filtered through a CELITE® pad, washed with additional 30ml of DCM and the filtrate concentrated and purified by column chromatography (0-10% EtOAc/hexane; 120g column). 5-Bromo-2-(3,5-dimethylpiperidin-1-yl)aniline (4.97 g, 17.55 mmol, 92% yield) was obtained as a light yellow oil. LC/MS, m/z = 283.0(M+1). HPLC Rt = 1.01 min. LC/MS (BEH C18 2.1X 50mm, 1.7u, 0 to 100 B in 1 min with 0.5 min hold time, Flow rate = 1 ml/min, detection at 254 nm, Solvent A: 100% water / 0.1% TFA; Solvent B: 100% ACN/ 0.1% TFA).
    • 235C. 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-(3,5-dimethylpiperidin-1-yl)aniline
  • Figure imgb1020
  • A mixture of 5-bromo-2-(3,5-dimethylpiperidin-1-yl)aniline (235B) (4.8 g, 16.95 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (4.98 g, 22.03 mmol), PdCl2(dppf)-CH2Cl2 Adduct (0.372 g, 0.508 mmol) and potassium acetate (4.99 g, 50.8 mmol) in DMSO (Volume: 30 mL) was evacuated and filled with nitrogen three times, then heated at 80 °C for 4h. The completed reaction was cooled to rt and the reaction mixture loaded on a silica gel plug (300g), and washed with (20% EtOAc/hexane). The resulting organic solution was concentrated and redissolved in DCM (5ml), and purified by column chromatography (0-20% EtOAc/hexane; 120g column). 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-(3,5-dimethylpiperidin-1-yl)aniline (4.07 g, 12.87 mmol, 76% yield) was obtained as a light brown solid. LC/MS, m/z = 249.0(M+1). HPLC Rt = 0.64min. (boronic acid) LC/MS (BEH C18 2.1X 50mm, 1.7u, 0 to 100 B in 1 min with 0.5 min hold time, Flow rate = 1 ml/min, detection at 254 nm, Solvent A: 100% water / 0.1% TFA; Solvent B: 100% ACN/ 0.1% TFA).
    • 235D. 4-(3,5-Dimethylpiperidin-1-yl)-2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-3-amine
  • Figure imgb1021
  • A mixture of toluene (Ratio: 2.250, Volume: 18 mL) and water (Ratio: 1.000, Volume: 8 mL) was degassed by purges with nitrogen (3x). 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-(3,5-dimethylpiperidin-1-yl)aniline (235C) (3 g, 9.49 mmol), 5-(2-bromophenyl)-2-trityl-2H-tetrazole (4.03 g, 8.62 mmol) and sodium carbonate (1.828 g, 17.25 mmol) were added, and the reaction mixture was purged (bubble) with nitrogen. Pd(Ph3P)4 (0.997 g, 0.862 mmol) was added at last. This mixture was degassed (3x) and the reaction mixture was heated at 80 °C under a nitrogen atmosphere for 14h, cooled to room temperature, and the resulting mixture was extracted with DCM (3x 60ml), washed with water and brine, dried over anhydrous Na2SO4 and the residue was purified by column chromatography (120g, 0% to 30% EtOAc in hexane) to obtain the product 4-(3,5-dimethylpiperidin-1-yl)-2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-3-amine (3.31 g, 5.60 mmol, 65.0% yield) as a light yellow solid. LC/MS, m/z = 591.3(M+1). HPLC Rt = 1.18 min. LC/MS (BEH C18 2.1X 50mm, 1.7u, 0 to 100 B in 1 min with 0.5 min hold time, Flow rate = 1 ml/min, detection at 254 nm, Solvent A: 100% water / 0.1% TFA; Solvent B: 100% ACN/ 0.1% TFA).
    • 235E. 1-(4-((3,5-Dimethylpiperidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1022
  • To a solution of 4-(3,5-dimethylpiperidin-1-yl)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-amine (235D) (59 mg, 0.100 mmol) in THF (1 mL) was added 1-isocyanato-4-methylbenzene (0.016 mL, 0.130 mmol). The solution was stirred 2h at RT. 4N HCl in dioxane (0.100 mL, 0.399 mmol) was added to the reaction mixture and the resulting mixture was heated at 50 °C for 10min, cooled to room temperature and concentrated. The residue was purified by HPLC, Column: Waters XBridge C18, 19 x 250 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain 1-(4-((3,5-dimethylpiperidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea (37.8 mg, 78% yield). LC/MS, m/z = 482.5(M+1). HPLC Rt = 0.94 min. LC/MS (BEH C18 2.1X 50mm, 1.7u, 0 to 100 B in 1 min with 0.5 min hold time, Flow rate = 1 ml/min, detection at 254 nm, Solvent A: 100% water / 0.1% TFA; Solvent B: 100% ACN / 0.1% TFA). 1H NMR (500MHz, methanol-d4) δ 8.01 - 7.94 (m, 1H), 7.75 - 7.70 (m, 1H), 7.68-7.62 (m, 3H), 7.60 - 7.50 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 3.01 (s, 2H), 2.94 - 2.80 (m, 2H), 2.32 (s, 3H), 2.21 - 1.92 (m, 2H), 1.59 - 1.39 (m, 2H), 1.16 - 0.86 (m, 6H).
    • Examples 236 and 237
  • Following the procedure of Example 235, Part E, employing the R9NCO substituent listed below, the following compounds were obtained.
    Figure imgb1023
    Example No. R9 [M+H]+ HPLC RT
    236
    Figure imgb1024
         		486.4 0.92v
    237
    Figure imgb1025
         		486.4 0.91v
    • Example 238 1,1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(pyridin-2-yl)urea
  • Figure imgb1026
    • 238A. 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine
  • Figure imgb1027
  • 4-Bromo-N1,N1-diisobutylbenzene-1,2-diamine (15.0 g, 50.1 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (20.38 g, 90.0 mmol), PdCl2(dppf)-CH2Cl2Adduct (1.842 g, 2.256 mmol), and potassium acetate (22.14 g, 226 mmol) were combined in a 250 mL RB flask, and DMSO (Volume: 150 mL) was added. The flask was evacuated and filled with argon 3x, then heated at 80 °C for 16h. The reaction was cooled to RT diluted with ethyl acetate and filtered. The filtrate was washed with water, dried, and concentrated to afford crude solid. Chromatography on silica gel (EtOAc-hexanes gradient) afforded 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (13.0 g, 78% yield) as a white solid. MS(ES): m/z = 265. (These mass spectra correspond to [M+H]+ for free boronic acid. No significant [M+H]+ is seen for the parent compound.) 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (d, 1 H, J = 1.2 Hz), 6.92-6.96 (m, 2H), 4.66 (brs, 2 H), 3.70 (s, 4H), 2.57 (d, 4H, J = 7.2 Hz), 1.66-1.69 (m, 2H), 0.94 (s, 6H), 0.84 (d, 12H, J = 6.8 Hz).
    • 238B. 3'-Amino-4'-(diisobutylamino)biphenyl-2-carbonitrile
  • Figure imgb1028
  • 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (238A) (7.5 g, 22.57 mmol), 2-bromobenzonitrile (4.93 g, 27.1 mmol), PdCl2(dppf)-CH2Cl2Adduct (3.69 g, 4.51 mmol) and potassium phosphate, tribasic (14.37 g, 67.7 mmol) were added to a 250 mL RB flask, which was evacuated and filled with argon 3 x followed by 2 mL of dioxane. The reaction mixture was heated at 80 °C for 16h. The reaction was cooled to room temperature, concentrated in dioxane, diluted with ethyl acetate, washed with water, dried, and concentrated to afford crude solid. Chromatography on silica gel (EtOAc-hexanes gradient) afforded 3'-amino-4'-(diisobutylamino)biphenyl-2-carbonitrile (6.2 g, 85.0% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.72 (dd, 1H, J = 8.0, 1.2 Hz), 7.58-7.61 (m, 1H), 7.50 (dd, 1 H, J = 8.0, 1.2 Hz), 7.37-7.39 (m, 1H), 7.14 (t, 1H), 7.13-7.15 (m, 1H), 6.89-6.92 (m, 2H), 4.12 (2H, brs), 2.65 (d, 4H, J = 7.2 Hz), 1.77-1.84 (m, 2H), 0.92 (d, 12H, J = 6.4 Hz). MS(ES): m/z = 322.2 [M+H]+.
    • 238C. N4,N4-Diisobutyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine
  • Figure imgb1029
  • 3'-Amino-4'-(diisobutylamine)biphenyl-2-carbonitrile (238B) (3.0 g, 9.33 mmol) and azidotributyltin (17.90 mL, 65.33 mmol) in toluene (60 mL) were heated at 110 °C for 40 hours, cooled to room temperature and washed with 10% KF aqueous solution, dried and concentrated to afford crude liquid product. Chromatography on silica gel (EtOAc-hexanes gradient) afforded N4,N4-diisobutyl-2'-(1H-tetrazol-5-yl) biphenyl-3,4-diamine (3.5 g) as yellow oil. MS(ES): m/z = 365.2 [M+H]+.
    • 238. 1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyridin-2-yl)urea
  • Figure imgb1030
  • To the stirred solution of N4,N4-diisobutyl-2'-(1H-tetrazol-5-yl)biphenyl-3,4-diamine (238C) (500 mg, 1.372 mmol) in DCM (3.0 mL) was added 4-nitrophenyl carbonochloridate (332 mg, 1.646 mmol) dropwise and refluxed for 1h. Reaction progress was detected by TLC and LCMS. The reaction mixture was concentrated to afford the crude carbamate. (Note: This intermediate was carried forward for the next step without purification.) The yellow residue (4-nitrophenyl(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)carbamate, 60.0 mg, 0.113 mmol) was taken up in DCE (1.0 mL). The solution was treated with Et3N (0.016 mL, 0.113 mmol) then pyridin-2-amine (10.66 mg, 0.113 mmol), stirred overnight at RT, and purified by preparative HPLC. Concentration of appropriate fractions afforded 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyridin-2-yl)urea (18 mg, 32.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.30 (brs, 1H), 9.84 (s, 1H), 8.22 (dd, 1H, J = 18.4, 1.2 Hz), 7.53-7.76 (m, 5H), 7.08-7.14 (m, 2H), 6.99-7.02 (m, 1H), 6.57 (dd, 1H, J = 8.4, 2.4 Hz), 2.84 (d, 4H, J = 6.8 Hz), 1.67-1.73 (m, 2H), 0.80 (d, 12H, J = 6.8 Hz). MS(ES): m/z = 485.4 [M+H]+,
    • Example 239 1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyrimidin-2-yl)urea
  • Figure imgb1031
    • 239A. N4,N4-diisobutyl-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine
  • Figure imgb1032
  • A mixture of toluene (12.5 mL) and water (5.0 mL) was degassed for 10 minutes. 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (2.48 g, 7.49 mmol), 5-(2-bromophenyl)-2-trityl-2H-tetrazole (2.5 g, 5.35 mmol), sodium carbonate (1.13 g, 10.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.371 g, 0.321 mmol) were added. This mixture was degassed under N2 atmosphere and heated at 80 °C for overnight. The reaction was cooled to room temperature, concentrated in toluene, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated and purified on silica gel (EtOAc/hexane gradient) to afford N4,N4-diisobutyl-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine (2.4 g) as an off-white solid. MS(ES): m/z = 607.4 [M+H]+.
    • 239B. 4-Nitrophenyl (4-(diisobutylamino)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)carbamate
  • Figure imgb1033
  • N4,N4-Diisobutyl-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine (0.1 g, 0.165 mmol) and 4-nitrophenyl carbonochloridate (0.033 g, 0.165 mmol) were taken in DCM (1 mL) and refluxed for 1h. The progress of the reaction was checked by LCMS. The solvent was removed to give 4-nitrophenyl (4-(diisobutylamino)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)carbamate (0.110 g). MS(ES): m/z = 772.2 [M+H]+.
    • 239C. 1-(4-(Diisobutylamino)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyrimidin-2-yl) urea
  • Figure imgb1034
  • To a slurry of sodium hydride (4.76 mg, 0.194 mmol) in THF (0.5 mL) was added a solution of pyrimidin-2-amine (8.87 mg, 0.093 mmol) in THF (0.5 mL) at 0 °C. The reaction mixture was stirred for 15 minutes, and 4-nitrophenyl (4-(diisobutylamino)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)carbamate (60 mg, 0.078 mmol) in THF (1.0 mL) added. The reaction mixture was slowly brought to room temperature, and stirred for 1h. The progress of the reaction was checked by TLC. No starting material was observed. The reaction mixture was quenched with ice cold water, extracted with ethyl acetate twice, the combined organic layer was washed with water, brine, dried over sodium sulfate and concentrated to give 1-(4-(diisobutylamino)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyrimidin-2-yl) urea (60 mg). MS(ES): m/z = 728.8 [M+H]+.
    • 239. 1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyrimidin-2 - yl)urea
  • Figure imgb1035
  • To a solution of 1-(4-(diisobutylamino)-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyrimidin-2-yl)urea (100 mg, 0.137 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.49 mmol) at 0 °C. The reaction mixture was brought to RT and stirred for 1h. The progress of the reaction was monitored by TLC. The complete conversion of starting material was observed. The reaction mixture was purified by silica gel column chromatography (230-400 mesh) using EtOAc/pet ether gradient. The fractions were concentrated to give the 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyrimidin-2-yl)urea (50 mg; 67.6% by LCMS), which was purified by reverse phase HPLC and freeze-dried to give 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(pyrimidin-2-yl)urea (12 mg) as an off-white solid. MS(ES): m/z = 486.2 [M+H]+.
    • Examples 240 to 249
  • Following the procedure of Example 239 using appropriate trityl-tetrazole and dioxaborinane starting materials, the following compounds were prepared. Table 12
    Figure imgb1036
    Ex. No. Name NR7R8 R9 HPLC Ret Time (M+H)+ / (M-1)
    240 1-(4-(diisobutylamino)-2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(1-(4-fluorophenyl)-2-methylpropan-2-yl)urea
    Figure imgb1037
    Figure imgb1038
         		20.07t 558.4
    241 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-ethynylphenyl)urea
    Figure imgb1039
    Figure imgb1040
         		19.86t 508.2
    242 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-(prop-2-yn-1-yloxy)phenyl) urea
    Figure imgb1041
    Figure imgb1042
         		19.54t 538.4
    243 1-(4-chloro-2,6-difluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1043
    Figure imgb1044
         		19.96t 554
    244 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(prop-2-yn-1-yloxy)phenyl) urea
    Figure imgb1045
    Figure imgb1046
         		18.91t 536.2
    245 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-isobutylurea
    Figure imgb1047
    Figure imgb1048
         		10.80t 464.4
    246 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-isopropylurea
    Figure imgb1049
    Figure imgb1050
         		10.27t 450.4
    247 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(isoquinolin-5-yl)urea
    Figure imgb1051
    Figure imgb1052
         		8.80t 533.2
    248 2-(3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)ureido)-N-methylbenzamide
    Figure imgb1053
    Figure imgb1054
         		18.33t 539.2
    249 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(4-trifluoromethyl)phenyl) urea
    Figure imgb1055
    Figure imgb1056
         		23.41t 550.0
    • Example 250 1-(3-Cyano-4-fluorophenyl-3-(4-diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1057
    Figure imgb1058
  • To the stirred solution of N4,N4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3,4-diamine (238E) (30 mg, 0.081 mmol) in DCM (2.0 mL) was added 2-fluoro-5-isocyanatobenzonitrile (13 mg, 0.082 mmol). The reaction was stirred at RT for 16 h. Solvent was removed in vacuo and the residue purified by prep. HPLC. The concentration of the appropriate fractions and freeze drying afforded 1-(3-cyano-4-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea (43.0 mg, 100% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.82 (s, 1H), 7.97-8.01 (m, 2H), 7.88 (d, 1H, J = 2.0 Hz), 7.47-7.71 (m, 6H), 7.48 (d, 1H, J = 8.4 Hz), 6.44 (dd, 1 H, J = 8.0, 2.0 Hz), 2.68 (d, 4H, J = 6.8 Hz), 1.64-1.67 (m, 2H), 0.84 (d, 12H, J = 6.4 Hz). MS(ES): m/z = 527.2 [M+H]+.
    • Synthesis of 2-fluoro-5-isocyanatobenzonitrile
  • Figure imgb1059
  • To a solution of 5-amino-2-fluorobenzonitrile (30 mg, 0.220 mmol) in DCM (2.0 mL) at 0 °C was added sodium carbonate (117 mg, 1.102 mmol) and phosgene (0.047 mL 0.441 mmol). The reaction was stirred at RT for 1h. MS(ES): m/z = 195, (These mass spectra correspond to [M+H]+ for methyl carbamate of the product. No significant [M+H]+ was seen for the parent compound. The above reaction mixture was filtered, concentrated under reduced pressure and used for the next step without purification.
    • Examples 251 to 276
  • Following the procedure of Example 250 employing the appropriate R9NCO, the following compounds were prepared. Table 13
    Figure imgb1060
    Ex. No. Name NR7R8 R9 HPLC Ret Time (M+H)+ / (M-1)
    251 1-(3-chloro-5-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1061
    Figure imgb1062
         		20.97t 536.2
    252 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-fluoro-3-methoxyphenyl)urea
    Figure imgb1063
    Figure imgb1064
         		18.81t 532.3
    253 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-(oxazol-5-yl)phenyl)urea
    Figure imgb1065
    Figure imgb1066
         		11.34t 549.2
    254 4-chloro-3-(3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)ureido)benzamide
    Figure imgb1067
    Figure imgb1068
         		10.54t 559
    255 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(oxazol-5-yl)phenyl)urea
    Figure imgb1069
    Figure imgb1070
         		18.21t 549.2
    256 1-(2-(1H-1,2,4-triazol-1-yl)phenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1071
    Figure imgb1072
         		10.81t 551.3
    257 1-(3-azidophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1073
    Figure imgb1074
         		20.10t 525.4
    258 1-(3-bromo-4-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1075
    Figure imgb1076
         		20.54t 580.2
    259 1-(benzo[b]thiophen-5-yl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1077
    Figure imgb1078
         		20.10t 538.0
    260 1-(4-cyano-2-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-y1)-[1,1 biphenyl]-3-yl)urea
    Figure imgb1079
    Figure imgb1080
         		19.19t 527.2
    261 1-(4-cyano-3-methoxyphenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1 biphenyl]-3-yl)urea
    Figure imgb1081
    Figure imgb1082
         		18.97t 537.2
    262 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-(dimethylamino)phenyl) urea
    Figure imgb1083
    Figure imgb1084
         		9.61t 527.2
    263 1-(2,3-difluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1085
    Figure imgb1086
         		19.62t 520.2
    264 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-fluoro-4-methylphenyl)urea
    Figure imgb1087
    Figure imgb1088
         		19.68t 516.2
    266 3-(3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)ureido)benzenesulfon amide
    Figure imgb1089
    Figure imgb1090
         		10.42t 563.2
    267 1-(3-(1H-imidazol-1-yl)phenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1091
    Figure imgb1092
         		9.49t 550.4
    268 1-(cyclohexylmethyl)-3 - (4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1093
    Figure imgb1094
         		20.03t 502.2
    269 1-(4-(diisobutylamino)-2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(prop-2-yn-1-yloxy)phenyl)ure
    Figure imgb1095
    Figure imgb1096
         		19.71t 538.4
    270 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(piperidin-1-yl)phenyl)urea
    Figure imgb1097
    Figure imgb1098
         		18.26t 567.4
    271 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl) urea
    Figure imgb1099
    Figure imgb1100
         		20.47t 570.2
    272 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-fluoro-2-isopropoxyphenyl)urea
    Figure imgb1101
    Figure imgb1102
         		20.69t 560.2
    273 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-(trifluoromethoxy)pheny l)urea
    Figure imgb1103
    Figure imgb1104
         		20.38t 568.2
    274 1-(2-cyclopropylphenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1105
    Figure imgb1106
         		20.70t 524.2
    275 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-fluoro-2-hydroxyphenyl)urea
    Figure imgb1107
    Figure imgb1108
         		17.98t 516.2
    276 1-(2,3-dihydro-1H-inden-4-yl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1109
    Figure imgb1110
         		20.12t 524.2
  • The urea analogs of Examples 277 to 279 were prepared by the following procedure. Table 14
    Figure imgb1111
    Ex. No. Name NR7R8 R9 HPLC Ret Time (M+H)+/ (M-1)
    277 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-ethynylphenyl)urea
    Figure imgb1112
    Figure imgb1113
         		20.16t 506.2
    278 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-ethynylphenyl)urea
    Figure imgb1114
    Figure imgb1115
         		19.98t 506.2
    279 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-fluoro-3-(methylsulfonyl)phenyl) urea
    Figure imgb1116
    Figure imgb1117
         		18.02t 578.2
  • The urea analogs of Examples 280 to 287 were prepared using the method described herein, i.e., the preparation of 2 from 2A, from aniline intermediates A and the appropriate isocyanates R9NCO. Table 15
    Figure imgb1118
    Ex. No. Name NR7R8 R9 HPLC Ret Time (M+H)+/ (M-1)
    280 1-(2-(difluoromethoxy) phenyl)-3-(4-(diisobutyl amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb1119
    Figure imgb1120
         		19.84t 550.3
    281 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-methoxyphenyl)urea
    Figure imgb1121
    Figure imgb1122
         		19.27t 514.3
    282 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-(1,1'-biphenyl]-3-yl)-3-(2,4,6-trifluorophenyl)urea
    Figure imgb1123
    Figure imgb1124
         		18.89t 536.2
    283 1-(2,6-difluorophenyl)-3-(4-(diisobutylamino)-2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1125
    Figure imgb1126
         		18.72t 518.2
    284 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-fluoro-4-(methylsulfonyl) phenyl)urea
    Figure imgb1127
    Figure imgb1128
         		17.93t 580.1
    285 1-(4-azidophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1129
    Figure imgb1130
         		19.63t 523.2
    286 1-(3-chloro-4-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
    Figure imgb1131
    Figure imgb1132
         		20.51t 534.0
    287 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-fluoro-4-methylphenyl)urea
    Figure imgb1133
    Figure imgb1134
         		19.75t 516.2
    • Example 288 1-(4-(Diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2,4,4-trimethylpentan-2-yl)urea
  • Figure imgb1135
    Figure imgb1136
  • To a solution of N4,N4-diisobutyl-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine (30 mg, 0.082 mmol) in THF (0.3 mL) was added 2,4,4-trimethylpentan-2-amine (15.96 mg, 0.123 mmol) and CDI (40 mg, 0.247 mmol). The reaction mixture was refluxed overnight. The progress of the reaction was checked by TLC and O-LCMS. Unreacted starting material was observed. CDI (1.0 eq) was added to the reaction mixture which was refluxed. The complete consumption of starting material was observed. The reaction mixture was diluted with EtOAc, washed with water, the organic layer collected, dried over anhydrous Na2SO4, filtered and excess solvent was evaporated under reduced pressure. The resultant crude material was purified by reverse phase HPLC and freeze-drying afforded 1-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2,4,4-trimethylpentan-2-yl)urea (6.0 mg, 13.27% yield) as a pale yellow solid. LCMS MS(ES): m/z = 520.2 [M+H]+.
    • Example 289 1-(4-(Benzyl(isobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1137
  • The compound was prepared from N4-benzyl-N4-isobutyl-2'-(2-trityl-2H-tetrazol-5-yl) biphenyl-3, 4-diamine by the general procedure used for the conversion of A to IIA as set out prior to Examples 280 to 287 and followed by detritylation (DCM, TFA, 1 hr). MS(ES): m/z=531.2 [M+H]+, HPLC Tr: 19.8.
    • Example 290 1-(4-(Benzyl(isobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea
  • Figure imgb1138
  • The compound was prepared from N4-benzyl-N4-isobutyl-2'-(2-trityl-2H-tetrazol-5-yl) biphenyl-3, 4-diamine by the general procedure used for the conversion of A to IIA as set out prior to Examples 280 to 287 and followed by detritylation (DCM, TFA, 1 hr). MS(ES): m/z =602.2 [M+H]+, HPLC Tr: 20.52.
    • Example 291 1-(4-(Benzyl(isobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-cyclopropylphenyl)urea
  • Figure imgb1139
  • The compound was prepared from N4-benzyl-N4-isobutyl-2'-(2-trityl-2H-tetrazol-5-yl) biphenyl-3, 4-diamine by the general procedure used for the synthesis of Example 250 and followed by detritylation (DCM, TFA, 1 hr). MS(ES): m/z =556.2 [M-H], HPLC Tr: 21.03.
  • Compound 292was prepared employing methodology described herein. Table 16
    Ex No. Name NR7R8 R9 HPLC Ret Time (M+H)+/ (M-1)
    292 1-(4-(benzyl(isobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1140
    Figure imgb1141
         		19.80t 531.2
    • Example 295 1-(4-(Phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-(trifluoromethyl)phenyl)urea
  • Figure imgb1142
    • 295A. 1-(5-Bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(2-(trifluoromethyl)phenyl)urea
  • Figure imgb1143
  • To a stirred solution of 4-bromo-N1-phenethyl-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (30 mg, 0.077 mmol) in DCM was added 1-isocyanato-2-(trifluoromethyl)benzene (17 mg, 0.093 mmol). The reaction mixture was stirred overnight. The reaction mixture was concentrated to give 1-(5-bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (35 mg). MS(ES): m/z = 576.1 [M+H]+.
    • 295. 1-(4-(Phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)-3-(2-(trifluoromethyl)phenyl)urea
  • Employing procedures described here, the title compound was prepared from 1-(5-bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (295A). MS(ESI-) m/z = 638.2 [M-H].
    • Example 296 1-(4-Cyclopropyl-3-fluorophenyl)-3-(4-phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
  • Figure imgb1144
    • 296A. 1-(5-Bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(4-cyclopropyl-3 -fluorophenyl)urea
  • Figure imgb1145
  • To a stirred solution of 4-bromo-N1-phenethyl-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (30 mg, 0.077 mmol) in DCM added 4-cyclopropyl-3-fluoroaniline (14 mg, 0.093 mmol) and CDI (25 mg, 0.155 mmol). The reaction mixture was heated at 40 °C for 48 hours. The reaction mixture was diluted with DCM and washed with water, brine solution, the organic layer dried over Na2SO4 and concentrated to provide 1-(5-bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(4-cyclopropyl-3-fluorophenyl)urea (35 mg). 1H NMR (400 MHz, CDCl3) δ ppm 8.49 (d, 1H, J = 2.4 Hz), 7.36-7.40 (m, 2H), 7.21-7.31 (m, 4H), 7.12-7.15 (m, 2H), 7.06 (d,1H, J = 8.4 Hz), 6.81-6.90 (m, 2H), 3.15-3.21 (m, 4H), 2.72-2.76 (m, 2H), 2.01-2.08 (m, 2H), 1.22-1.25 (m, 1H), 0.92-0.97 (m, 2H), 0.66-0.70 (m, 2H). MS(ES): m/z = 564.2 [M+H]+.
    • 296. 1-(4-Cyclopropyl-3-fluorophenyl)-3-(4-(phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)biphenyl-3-yl)urea
  • Figure imgb1146
  • The title compound was prepared from 1-(5-bromo-2-(phenethyl(3,3,3-trifluoropropyl)amino)phenyl)-3-(4-cyclopropyl-3-fluorophenyl)urea (296A) as outlined above. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.53 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.56-7.72 (m, 4H), 7.43 (dd, 1H, J = 12.8, 2.0 Hz), 7.41-7.45 (m, 3H), 7.13-7.17 (m, 3H), 6.89-7.00 (m, 2H), 6.62 (dd, 1H, J = 8.4, 2.0 Hz), 3.15-3.22 (m, 4H), 2.51-2.63 (m, 2H), 2.33-2.39 (m, 2H), 1.93-1.97 (m, 1H), 0.89-0.93 (m, 2H), 0.65-0.67. MS(ES): m/z = 630.2 [M+H]+,
    • Examples 297 to 304
  • The following compounds were prepared using the procedure shown below with the appropriate starting materials. Table 17
    Figure imgb1147
    Ex No. Name NR7R8 R9 HPLC Ret Time (M+H)+ / (M-1)
    297 1-(4-((4-chlorobenzyl)(4,4,4-trifluorobutyl)amino)-2'-(l1-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-cyclopropyl-3-fluorophenyl)urea
    Figure imgb1148
    Figure imgb1149
         		21.77t 664.2
    298 1-(4-cyclopropylphenyl)-3-(4-(phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1150
    Figure imgb1151
         		20.27t 612.4
    299 1-(4-cyclopropylphenyl)-3-(4-((4-fluoro-2-(trifluoromethyl)benzyl)(3,3, 3-trifluoropropyl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1152
    Figure imgb1153
         		20.98t 684.5
    300 1-(4-((4-fluoro-2-(trifluoromethyl)benzyl)(3,3, 3-trifluoropropyl)amino)-2 '-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-fluoro-4-(trifluoromethyl) phenyl)urea
    Figure imgb1154
    Figure imgb1155
         		20.79t 730.4
    301 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethoxy) benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(2-fluoro-4-(trifluoromethyl) phenyl)urea
    Figure imgb1156
    Figure imgb1157
         		20.71t 728.3
    302 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethoxy) benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(4-cyclopropylphenyl)urea
    Figure imgb1158
    Figure imgb1159
         		21.21t 682.5
    303 1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(4-((pyridin-2-ylmethyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1160
    Figure imgb1161
         		16.28t 645.3
    304 1-(4-cyclopropylphenyl)-3-(4-((pyridin-2-ylmethyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1162
    Figure imgb1163
         		15.60t 599.4
    • Examples 305 to 307
  • Starting from cis-N-isobutyl-4-(trifluoromethyl)cyclohexanamine (lxy, Table 3b) and 2-fluoro-5-bromonitrobenzene the following compounds of the generic structure below with substituents specified in the table were prepared using the procedure for the conversion of 1B to Example 1.
    Figure imgb1164
    Ex No. Name R HPLC Ret Time (M+H)+
    305 1-(4-(isobutyl(4-(trifluoromethyl)cyclohexyl)a mino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1165
         		2.31j 592
    306 5-fluoro-4'-(isobutyl(4-(trifluoromethyl)cyclohexyl)a mino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb1166
         		2.12j 586
    307 4'-(isobutyl(4-(trifluoromethyl)cyclohexyl)a mino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
    Figure imgb1167
         		2.28j 568
    • Example 308 1-(4-(diisobutylamino)-2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(5-methylpyrazin-2-yl)urea
  • Figure imgb1168
  • A reaction vial was charged with N4,N4-diisobutyl-2'-(2-trityl-2H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine ((38A), 99.3 mg, 0.164 mmol) in dry THF (2 mL) under nitrogen. This solution was treated with 4-nitrophenyl chloroformate (36.3 mg, 0.180 mmol) and stirred for 0.5 hours. The reaction was then treated with 5-methylpyrazin-2-amine (53.6 mg, 0.491 mmol) and triethylamine (68.4 µl, 0.491 mmol). The reaction was warmed to 50°C overnight then cooled and treated with 100 uL of 5-6 M HCl in isopropanol. This mixture was briefly warmed to 50°C, stirred overnight at RT, then concentrated and partially purified by reverse-phase HPLC (methanol-water gradient +0.1% TFA). This material was further purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporationto afford 0.012 g (15%) of 1-(4-(diisobutylamino)-2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(5-methylpyrazin-2-yl)urea. MS(ES): m/z = 500 [M+H]+. HPLC ret. time: 1.71j.
    • Example 309 4'-(Diisobutylamino)-3-methyl-3'-(3-(4-(trifluoromethoxy)phenyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1169
    • 309A 4'-Fluoro-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1170
  • A reaction vial was charged with DMF (5.0 mL), 4-bromo-1-fluoro-2-nitrobenzene (304 mg, 1.382 mmol) and 2-boronobenzoic acid (459 mg, 2.76 mmol). Nitrogen was bubbled through the solution for 20 minutes. A solution of potassium carbonate (2764 µl, 2.76 mmol) (1.0 M solution) was added and bubbling with nitrogen continued for a few more minutes. Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.069 mmol) was added and the vial was sealed. The reaction was heated to 90 °C for 3 hours. The light orange reaction was cooled and quenched with 10% acetic acid. Some precipitate formed. The reaction was concentrated under a stream of nitrogen. The reaction was filtered and the yellow solid rinsed with water. This first crop contained product but was not pure by TLC on silica gel (1:1 ethyl acetate-hexanes +0.5% acetic acid). After standing, additional solid precipitates from the mother liquor. Filtration provided 4'-fluoro-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (153 mg, 42%) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ 13.10 - 12.87 (m, 1H), 8.06 (dd, J=7.1, 2.3 Hz, 1H), 7.90 (dd, J=7.8, 1.2 Hz, 1H), 7.77 (ddd, J=8.6, 4.4, 2.4 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.70 - 7.61 (m, 2H), 7.59 - 7.52 (m, 1H), 7.46 (dd, J=7.6, 0.9 Hz, 1H).
    • 309B 4'-Fluoro-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1171
  • A reaction vial was charged with 4'-fluoro-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (111 mg, 0.425 mmol), palladium(II) acetate (9.5 mg, 0.042 mmol), silver carbonate (234 mg, 0.850 mmol), lithium carbonate (62.8 mg, 0.850 mmol), t-Boc-L-phenylalanine (22.6 mg, 0.085 mmol), potassium methyltrifluoroborate (155 mg, 1.275 mmol). DMF (32.9 µL, 0.425 mmol) and a stirring bar. t-Butanol (3.0 mL) was added and the vial was evacuated and filled with nitrogen three times. The vial was sealed, and the reaction was stirred for 5 minutes at ambient temperature. The reaction was then warmed to 90 °C for three days. The cooled reaction was quenched with 2 mL 1 N hydrochloric acid and sonicated. Methylene chloride was added, and the reaction was filtered. The filtrate was transferred to a separatory funnel and partitioned between methylene chloride and water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by RP-HPLC (methanol-water gradient +0.1% TFA). Evaporation of the appropriate fractions gave 4'-fluoro-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (26 mg, 0.094 mmol, 22 % yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 13.31 (s, 1H), 8.11 (dd, J=7.1, 2.3 Hz, 1H), 7.82 (ddd, J=8.7, 4.4, 2.3 Hz, 1H), 7.70 (dd, J=11.2, 8.7 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.38 (d, J=6.0 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 2.38 (s, 3H). 19F NMR (376MHz, DMSO-d6) δ -121.18.
    • 309C 4'-(Diisobutylamino)-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1172
  • 4'-Fluoro-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (32 mg, 0.116 mmol) was dissolved in DMF (1 mL) and diisobutylamine (1 mL). The reaction was warmed to 110 °C and stirred for 4 hours. The cooled reaction was quenched with 10% acetic acid. A nice solid formed. The solid was filtered and rinsed with water. Air drying provided 4'-(diisobutylamino)-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (27.9 mg, 62%) as an orange solid. MS(ES): m/z = 385 [M+H]+.
    • 309D 3'-Amino-4'-(diisobutylamino)-3-methyl-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1173
  • A Parr bottle was charged with 4'-(diisobutylamino)-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid (26 mg, 0.068 mmol) in ethyl acetate (ca. 10 mL). 10% Pd/C (26 mg) was added and the vessel pressurized with 45 psi hydrogen. After 3 hours, the reaction was filtered and evaporated to give 20 mg of an orange solid. This material was used without purification in the subsequent reaction. MS(ES): m/z = 355 [M+H]+.
    • 309 4'-(Diisobutylamino)-3-methyl-3'-(3-(4-(trifluoromethoxy)phenyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1174
  • 3'-Amino-4'-(diisobutylamino)-3-methyl-[1,1'-biphenyl]-2-carboxylic acid (10 mg, 0.028 mmol) was dissolved in dry DMF (0.25 mL). 1-Isocyanato-4-(trifluoromethoxy)benzene (10 uL) was added and stirring continued for 4 hours. The reaction was then diluted with DMF (1.75 mL). The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 25-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 4'-(diisobutylamino)-3-methyl-3'-(3-(4-(trifluoro methoxy)phenyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid (8.0 mg, 50%).
    1H NMR (500MHz, DMSO-d6) δ 9.72 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.46 - 7.34 (m, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.28 - 7.22 (m, 2H), 7.19 (d, J=7.4 Hz, 1H), 7.03 (d, J=7.1 Hz, 1H), 2.71 (d, J=6.7 Hz, 4H), 2.34 (s, 3H), 1.70 (dt, J=13.1, 6.6 Hz, 2H), 0.89 (d, J=6.4 Hz, 12H). MS(ES): m/z = 558 [M+H]+.
    • Examples 315 to 345
  • Using the method shown below, the following compounds of the invention were prepared from aniline intermediates L and the appropriate isocyanate R9NCO. Table 18
    Figure imgb1175
    Ex. No. Name NR7R8 R9 HPLC Ret Time (M+H) +/ (M-1)
    315 1-(4-(3,3-difluoropyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1176
    Figure imgb1177
         		16.93t 476.2
    316 1-(4-(3,3-difluoropyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)pheny l)urea
    Figure imgb1178
    Figure imgb1179
         		18.18t 544.0
    317 1-(4-(5-benzyl-2,5-diazabicyclo[2.2.1]hepta n-2-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1180
    Figure imgb1181
         		8.80t 555.2
    318 1-(4-(5-benzyl-2,5-diazabicyclo[2.2.1]hepta n-2-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)pheny l)urea
    Figure imgb1182
    Figure imgb1183
         		14.93t 627.2
    319 1-(4-((4-chlorobenzyl)(4,4,4-trifluorobutyl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2,4-difluorophenyl)urea
    Figure imgb1184
    Figure imgb1185
         		20.55t 642
    320 1-(4-((4-chlorobenzyl)(4,4,4-trifluorobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1186
    Figure imgb1187
         		21.06t 620.2
    321 1-(4-((4-chlorobenzyl)(4,4,4-trifluorobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl)phenyl) urea
    Figure imgb1188
    Figure imgb1189
         		12.33t 674.2
    322 1-(4-((4-chlorobenzyl)(4,4,4-trifluorobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)pheny l)urea
    Figure imgb1190
    Figure imgb1191
         		21.02t 688.2
    323 1-(4-((4-fluorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)pheny l)urea
    Figure imgb1192
    Figure imgb1193
         		20.13t 660.2
    324 1-(2,4-difluorophenyl)-3-(4-((4-fluorobenzyl) (3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1194
    Figure imgb1195
         		19.25t 612
    Ex. No. Name NR7R8 R9 HPLC Ret Time (M+H) +/ (M-1)
    325 1-(4-((4-fluorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1196
    Figure imgb1197
         		19.87t 588.2
    326 1-(4-((4-fluorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl)phenyl) urea
    Figure imgb1198
    Figure imgb1199
         		11.69t 644.2
    327 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethyl) benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy) phenyl)urea
    Figure imgb1200
    Figure imgb1201
         		20.77t 710.2
    328 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethyl) benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl)phenyl) urea
    Figure imgb1202
    Figure imgb1203
         		20.11t 692
    329 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethyl) benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1204
    Figure imgb1205
         		20.64t 640.2
    330 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethyl) benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(2,4-difluorophenyl)urea
    Figure imgb1206
    Figure imgb1207
         		20.43t 662.2
    331 1-(4-(phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)pheny l)urea
    Figure imgb1208
    Figure imgb1209
         		20.85t 656.4
    332 1-(2,4-difluorophenyl)-3-(4-(phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1210
    Figure imgb1211
         		19.51t 608.2
    333 1-(4-(phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl)phenyl) urea
    Figure imgb1212
    Figure imgb1213
         		20.16t 638.2 (M-1)-
    334 1-(4-(phenethyl(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1214
    Figure imgb1215
         		19.79t 586.2
    335 1-(4-((2,4-dichlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl) phenyl)urea
    Figure imgb1216
    Figure imgb1217
         		20.46t 694.9
    336 1-(4-((2,4-dichlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2,4-difluorophenyl) urea
    Figure imgb1218
    Figure imgb1219
         		20.58t 662
    337 1-(4-((2,4-dichlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy) phenyl)urea
    Figure imgb1220
    Figure imgb1221
         		21.25t 710.9
    338 1-(4-((4-fluoro-2-(frifluoromethyl) benzyl)(3,3,3-trifluoropropyl)amino)-2'-(1 H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl)phenyl) urea
    Figure imgb1222
    Figure imgb1223
         		19.83t 712.3
    339 1-(4-((4-fluoro-2-(trifluoromethyl) benzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)pheny l)urea
    Figure imgb1224
    Figure imgb1225
         		20.46t 728.3
    340 1-(2,4-difluorophenyl)-3-(4-((4-fluoro-2-(trifluoromethyl)benzyl)( 3,3,3-trifluoropropyl) amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1226
    Figure imgb1227
         		19.58t 680.3
    341 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethoxy)benzyl )(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
    Figure imgb1228
    Figure imgb1229
         		20.57t 654
    342 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethoxy)benzyl )(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl)phenyl) urea
    Figure imgb1230
    Figure imgb1231
         		20.10t 708.2
    343 1-(4-((pyridin-2-ylmethyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy) phenyl)urea
    Figure imgb1232
    Figure imgb1233
         		16.06t 643.3
    344 1-(2,4-difluorophenyl)-3-(4-((pyridin-2-ylmethyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1234
    Figure imgb1235
         		14.48t 595.3
    345 1-(4-((pyridin-2-ylmethyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-(trifluoromethyl) phenyl)urea
    Figure imgb1236
    Figure imgb1237
         		14.63t 627.3
    • Examples 346 to 354
  • The following compounds were prepared employing the method outlined below employing appropriate starting materials. Table 19
    Figure imgb1238
    Ex. No. Name NR7R8 R9 HPLC Ret Time (M+H)+/ (M-1)
    346 1-(3-chloro-5-fluorophenyl)-3-(4-(diisobutylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1239
    Figure imgb1240
         		20.97t 536.2
    347 1-(4-cyclopropylphenyl)-3-(4-(3,3-difluoropyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1241
    Figure imgb1242
         		17.98t 502.2
    348 1-(4-(5-benzyl-2,5-diazabicyclo[2.2.1] heptan-2-yl)-2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-cyclopropylphenyl) urea
    Figure imgb1243
    Figure imgb1244
         		9.41t 583.4
    349 1-(4-((4-chlorobenzyl)(4,4,4-trifluorobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-cyclopropylphenyl)urea
    Figure imgb1245
    Figure imgb1246
         		21.33t 646.2
    350 1-(4-cyclopropylphenyl)-3-(4-((4-fluorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1247
    Figure imgb1248
         		20.67t 616.2
    351 1-(4-cyclopropyl-3-fluorophenyl)-3-(4-((2,4-dichlorobenzyl) (3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1249
    Figure imgb1250
         		16.70t 684.9
    352 1-(4-cyclopropyl-3-fluorophenyl)-3-(4-((4-fluoro-2-(trifluoromethyl)benzyl) (3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1251
    Figure imgb1252
         		20.85t 700.2 (M-1)-
    353 1-(2'-(1H-tetrazol-5-yl)-4-((4-(trifluoromethoxy)benzyl)(3,3 ,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(4-cyclopropyl-3-fluorophenyl)urea
    Figure imgb1253
    Figure imgb1254
         		20.79t 698 (M-H)-
    354 1-(4-cyclopropyl-3-fluorophenyl)-3-(4-((pyridin-2-ylmethyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
    Figure imgb1255
    Figure imgb1256
         		15.91t 617.5
    • Example 355 1-(4-(cyclohexyl(isobutyl)amino)-5',6-difluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1257
    • Part A: 1-(2'-cyano-4-(cyclohexyl(isobutyl)amino)-5',6-difluoro-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1258
  • The above compound was prepared from 1-(5-bromo-2-(cyclohexyl(isobutyl)amino)-4-fluorophenyl)-3-(p-tolyl)urea (Table 7) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile by the procedure used for conversion of 1C to 1. MS(ES): m/z = 517[M + H]+. HPLC Tr: 5.171.
    • 355. 1-(4-(cyclohexyl(isobutyl)amino)-5',6-difluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3 -yl)-3 -(p-tolyl)urea
  • Figure imgb1259
    • 355: 1-(4-(cyclohexyl(isobutyl)amino)-5',6-difluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • The compound was prepared from 1-(2'-cyano-4-(cyclohexyl(isobutyl)amino)-5',6-difluoro-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea by the general procedure used for the conversion of 7A into 7B. MS(ES): m/z = 560[M + H]+. HPLC Tr: 2.94q.
    • Example 356 1-(4-(cyclohexyl(2,2-difluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1260
    • Part A: 1-((4-bromo-2-nitrophenyl)(cyclohexyl)amino)propan-2-one
  • Figure imgb1261
  • A solution of 4-bromo-N-cyclohexyl-N-(2-methylallyl)-2-nitroaniline (0.05 g, 0.142 mmol) in dioxane (2 mL) was treated with osmium tetroxide (0.072 g, 7.08 µmol) and 2,6-lutidine (0.016 mL, 0.142 mmol) followed by a slurry of sodium periodate (0.121 g, 0.566 mmol) in water (0.5 mL). This mixture was stirred 3h at RT. then diluted with ether and washed twice with water. The org. phase was dried, stripped, and chromatographed on silica gel (gradient elution with ether-hexanes). Concentration of the appropriate fractions afforded 1-((4-bromo-2-nitrophenyl)(cyclohexyl)amino)propan-2-one as an oil. MS(ES): m/z = 275 [M + H]+. HPLC Tr: 4.471.
    • Part B: 4-bromo-N-cyclohexyl-N-(2,2-difluoropropyl)-2-nitroaniline
  • Figure imgb1262
  • A solution of 1-((4-bromo-2-nitrophenyl)(cyclohexyl)amino)propan-2-one (0.045 g, 0.127 mmol) in dichloromethane (0.5 ml) was treated with DAST (0.067 ml, 0.507 mmol) and stirred at RT. After 24h, additional DAST (0.1 mL) was added, and the reaction was stirred an additional 24h. The reaction was applied to a silica gel column (hexane) and eluted with a gradient of ether-hexane. Concentration of the appropriate fractions afforded 4-bromo-N-cyclohexyl-N-(2,2-difluoropropyl)-2-nitroaniline (0.04 g, 0.101 mmol, 80 % yield) as an orange oil. MS(ES): m/z = 297[M + H]+. HPLC Tr: 2.30p.
    • Part C: 1-(5-bromo-2-(cyclohexyl(2,2-difluoropropyl)amino)phenyl)-3-(p-tolyl)urea
  • Figure imgb1263
  • A solution of 4-bromo-N-cyclohexyl-N-(2,2-difluoropropyl)-2-nitroaniline (0.037 g, 0.098 mmol) in ethanol (3 mL) was treated with ammonium chloride (0.079 g, 1.471 mmol) and 0.3 mL of water. This mixture was stirred 10 min. at RT then treated with zinc (0.096 g, 1.471 mmol). The reaction was stirred 5 min. at RT then diluted with dichloromethane and filtered. The filtrate was washed with water, dried, and stripped to afford an oil. This was dissolved in 0.5 mL of THF and treated with 0.03 mL of p-tolyl isocyanate. The reaction was stirred 1h at RT. LCMS of the first step indiates that much hydroxylamine intermediate was present. The second step has proceeded to give a mixture of the desired urea and N-hydroxy urea. The reaction was diluted with 2 mL of ethanol and 0.2 mL of water followed by 0.05g of ammonium chloride and 0.1g of zinc. The reaction was stirred ON at RT. The reaction was concentrated and applied to a silica gel column. Gradient elution with ether-hexanes afforded 0.016 g (34%) of 1-(5-bromo-2-(cyclohexyl(2,2-difluoropropyl)amino)phenyl)-3-(p-tolyl)urea as a glass. MS(ES): m/z = 482[M+H]+. HPLC Tr: 4.461.
    • 356: 1-(4-(cyclohexyl(2,2-difluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1264
  • The title compound was prepared from 1-(5-bromo-2-(cyclohexyl(2,2-difluoropropyl)amino)phenyl)-3-(p-tolyl)urea and(2-(1H-tetrazol-5-yl)phenyl)boronic acid by the procedure used for conversion of 1C to 1. MS(ES): m/z = 546[M + H]+. HPLC Tr: 4.021.
    • Example 357 1-(2-fluorophenyl)-3-(4-(isobutylamino)-5-(1-phenylallyl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1265
    • Part A: 4-Bromo-1-(cinnamyloxy)-2-nitrobenzene
  • Figure imgb1266
  • To a stirred, cooled (-78 °C) solution of (E)-3-phenylprop-2-en-1-ol (2.415 g, 18.00 mmol) in THF (3 mL) was added n-butyllithium (5.76 mL, 14.40 mmol), dropwise over 4-5 min. The solution was stirred for 5 min. at -78 °C then treated with 4-bromo-1-fluoro-2-nitrobenzene (2.64 g, 12 mmol) and allowed to warm to RT with stirring. Stirring at RT was continued for 30 min, after which time the reaction was transferred into aq. HCl, and this mixture was extracted with ether. The organic extract was dried, stripped, and chromatographed on silica gel (gradient elution with ether-hexanes). Concentration of the appropriate fractions afforded an oily yellow solid. This was triturated with heptane to afford 4-bromo-1-(cinnamyloxy)-2-nitrobenzene (2.2 g, 52.1% yield) as a pale yellow powder, mp 95-97 °C. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13(d, 1 H, J = 2.4 Hz); 7.84(dd, 1 H, J = 9.0, 2.4 Hz); 7.47(d, 2 H, J = 7.3 Hz); 7.42(d, 1H, J = 9.2 Hz); 7.35(t, 2H, J = 7.4 Hz); 7.28(t, 1H, J = 7.8 Hz); 6.78(d, 1H, J = 16.1 Hz); 6.46(dt, 1H, J = 16.1, 5.8 Hz); 4.92(d, 2H, J = 5.9 Hz).
    • Part B: (+/-)-4-Bromo-2-nitro-6-(1-phenylallyl)phenol
  • Figure imgb1267
  • A solution of 4-bromo-1-(cinnamyloxy)-2-nitrobenzene (8A) (1.5 g, 4.49 mmol) in diglyme (3 mL) was placed under nitrogen and heated to 150 °C for 36h. The reaction was cooled and purified by flash chromatography (gradient elution with hexanes up to 15% ether-hexanes). Concentration of the appropriate fractions afforded 4-bromo-2-nitro-6-(1-phenylallyl)phenol (1.08 g, 68.4% yield) as an oily yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.73(br. s, 1H); 8.04(d, 1H, J = 2.4 Hz) 7.62(d, 1 H, J = 2.4 Hz); 7.31(t, 2 H, J = 7.4 Hz); 7.16-7.25(m, 3H); 6.39(ddd, 1H, J = 17.1, 10.1, 7.5 Hz); 5.23 (d, 1H, J = 10.1 Hz); 5.15(d, 1H, J = 7.3 Hz); 5.00(d, 1H, J = 17.2 Hz).
    • Part C: 2-(allyloxy)-5-bromo-1-nitro-3-(1-phenylallyl)benzene
  • Figure imgb1268
  • To a solution of 4-bromo-2-nitro-6-(1-phenylallyl)phenol (0.1 g, 0.299 mmol) in DMF (1 mL) was added potassium carbonate (0.124 g, 0.898 mmol) followed by 3-bromoprop-1-ene (0.145 g, 1.197 mmol). This mixture was brought to 60°C and stirred for 17h. The reaction was cooled, quenched with glacial HOAc, and purified by flash chromatography (gradient elution with ether-hexanes). Concentration of the appropriate fractions afforded 2-(allyloxy)-5-bromo-1-nitro-3-(1-phenylallyl)benzene (0.105 g, 89 % yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08(d, 1H, J = 2.2 Hz) 7.69(d, 1 H, J = 2.2 Hz); 7.33(dd, 2 H, J = 7.5, 7.3 Hz); 7.24(td, 1H, J = 7.5, 1.8 Hz); 7.19(d, 2H, J = 7.7 Hz); 6.34-6.44(m, 1H); 5.84-5.95(m, 1H); 5.21-5.32(m, 3H); 5.13(d, 1H, J = 7.0 Hz); 5.02(dd, 1H, J = 17.0, 1.1 Hz); 4.25-4.41(m, 2H).
    • Part D: 4-bromo-N-isobutyl-2-nitro-6-(1-phenylallyl)aniline
  • Figure imgb1269
  • A solution of 2-(allyloxy)-5-bromo-1-nitro-3-(1-phenylallyl)benzene (0.09 g, 0.240 mmol) in NMP (0.2 mL) was heated at 60°C for 20 min. LCMS suggests that LTN reaction has occurred. The solution was treated with 0.05 mL more isobutylamine and heated to 80°C for 2h. LCMS suggests that reaction is occurring to give two products. The reaction was cooled and purified by prep. HPLC (Axia Luna 30 x 100 mm column, MeOH-water-TFA gradient). Concentration of the appropriate (earlier-eluting) fractions afforded 4-bromo-N-isobutyl-2-nitro-6-(1-phenylallyl)aniline as a yellow oil. MS(ES): m/z = 391 [M + H]+. HPLC Tr: 5.431.
    • Part E: 4-bromo-N1-isobutyl-6-(1-phenylallyl)benzene-1,2-diamine
  • Figure imgb1270
  • A solution of 4-bromo-N-isobutyl-2-nitro-6-(1-phenylallyl)aniline (0.06 g, 0.154 mmol) in ethanol (4 mL) was treated with 0.4 mL of water, and the resulting mixture was stirred for 5 min. at RT. This stirred suspension was treated with zinc (0.151 g, 2.312 mmol), and after stirring 30 min. the reaction was diluted with dichloromethane and filtered. The filtrate was washed with water, dried, and stripped to afford 4-bromo-N1-isobutyl-6-(1-phenylallyl)benzene-1,2-diamine (0.055 g, 92 % yield) as a pale amber oil. MS(ES): m/z = 359[M + H]+. HPLC Tr: 4.351.
    • Part F: 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(2-fluorophenyl)urea
  • Figure imgb1271
  • A solution of 4-bromo-N1-isobutyl-6-(1-phenylallyl)benzene-1,2-diamine (0.033 g, 0.092 mmol) in THF (0.8 mL) was treated with 1-fluoro-2-isocyanatobenzene (0.025 g, 0.184 mmol). The reaction was stirred 30 min. at 60°C then cooled, concentrated, and purified by flash chromatography (gradient elution with ether-hexanes). Concentration of the appropriate fractions afforded 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(2-fluorophenyl)urea (0.04 g, 88 % yield) as a colorless solid. MS(ES): m/z = 498[M + H]+. HPLC Tr: 5.231.
    • 357. 1-(2-fluorophenyl)-3-(4-(isobutylamino)-5-(1-phenylallyl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1272
  • The title compound was prepared from 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(2-fluorophenyl)urea and(2-(1H-tetrazol-5-yl)phenyl)boronic acid by the procedure used for conversion of 1C to 1. MS(ES): m/z = 562[M + H]+. HPLC Tr: 4.021.
    • Example 358 1-(4-(isobutylamino)-5-(1-phenylallyl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1273
    • Part A: 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(p-tolyl)urea
  • Figure imgb1274
  • The title compound was prepared from 4-bromo-N1-isobutyl-6-(1-phenylallyl)benzene-1,2-diamine and 1-isocyanato-4-methylbenzene by the procedure used to prepare 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(2-fluorophenyl)urea. MS(ES): m/z = 492[M + H]+. HPLC Tr: 5.091.
    • 358: 1-(4-(isobutylamino)-5-(1-phenylallyl)-2'-(1H-tetrazol-5-yl)- [1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1275
  • The title compound was prepared from 1-(5-bromo-2-(isobutylamino)-3-(1-phenylallyl)phenyl)-3-(p-tolyl)urea and (2-(1H-tetrazol-5-yl)phenyl)boronic acid by the procedure used for conversion of 1C to 1. MS(ES): m/z = 558[M + H]+. HPLC Tr: 4.481.
    • Example 359 4-Chloro-3'-(3-(6-cyanopyridin-3-yl)ureido)-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1276
    • A. Methyl 3'-amino-4-chloro-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1277
  • 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (4B) (128 mg, 0.385 mmol), methyl 2-bromo-5-chlorobenzoate (80 mg, 0.321 mmol), PdCl2(dppf)-CH2Cl2Adduct (23.5 mg, 0.032 mmol) and potassium phosphate, tribasic (204 mg, 0.962 mmol) were added to a 2 dram vial which was then evacuated and filled with nitrogen 3x. Dioxane (2 mL) was added and the resultant mixture was purged with nitrogen for five minutes. The mixture was then heated at 100 °C for 20h. The reaction was cooled to rt, filtered and concentrated in vacuo before being purified via ISCO Companion (12g silica gel column with 0-10% EtOAc/hexane gradient) to afford the title compound as a clear oil (99.4 mg, 75%). 1H NMR (500MHz, CDCl3) δ 7.71 (d, J=2.2 Hz, 1H), 7.45 (dd, J=8.2, 2.1 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.66 (d, J=1.9 Hz, 1H), 6.60 (dd, J=8.0, 1.9 Hz, 1H), 4.17 (br. s., 2H), 2.65 (d, J=7.2 Hz, 4H), 1.79 (m, 2H), 0.93 (d, J=6.7 Hz, 12H). MS(ES): m/z = 389 [M+H]+.
    • B. 3'-Amino-4-chloro-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1278
  • To a mixture of methyl 3'-amino-4-chloro-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylate (99.4 mg, 0.256 mmol) in MeOH (1 mL) and THF (0.6 mL) was added LiOH (2M aq solution, 1.28 mL, 2.56 mmol). The resulting mixture was heated at 100 °C for thirty minutes, then cooled to room temperature and neutralized with HCl (1N in diethyl ether, 2.56 mL, 2.56 mmol). The mixture was concentrated to remove volatiles, then extracted with EtOAc (3x). The combined organic layers were concentrated in vacuo to afford the title compound as a brown solid (75 mg, 77%) which was used without further purification. MS(ES): m/z = 375 [M+H]+.
    • 359. 4-Chloro-3'-(3-(6-cyanopyridin-3-yl)ureido)-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1279
  • To a mixture of 5-aminopicolinonitrile (20 mg, 0.168 mmol) in anhydrous THF (1 mL) was added 4-nitrophenyl carbonochloridate (41 mg, 0.201 mmol). The mixture was stirred at 35 °C for twenty minutes to afford 4-nitrophenyl (6-cyanopyridin-3-yl) carbamate. MS(ESI+) m/z 285.2 (M + H)+. The entire reaction mixture was used without further purification.
  • To the 4-nitrophenyl (6-cyanopyridin-3-yl) carbamate reaction mixture was added 3'-amino-4-chloro-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylic acid (25 mg, 0.067 mmol), followed by TEA (0.04 mL, 0.267 mmol). The resulting mixture was stirred at 50°C for twenty minutes. After cooling to room temperature, the compound was purified via via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 150 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (17.7 mg, 51% yield). MS(ES): m/z = 520 [M+H]+, HPLC Tr: 1.73j.
    • Example 360 4-Chloro-3'-(3-(4-chloro-2-fluorophenyl)ureido)-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1280
  • To a mixture of 3'-amino-4-chloro-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylic acid (25 mg, 0.067 mmol) in anhydrous THF (0.5 mL) was added 4-chloro-2-fluoro-1-isocyanatobenzene (19 mg, 0.113 mmol). The resulting mixture was stirred at 50°C for ten minutes. After cooling to room temperature, the compound was purified via via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 150 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (28.1 mg, 76% yield). MS(ES): m/z = 546 [M+H]+, HPLC Tr: 2.03j.
    • Example 361 1-(4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1281
    • A. 1-(4-Bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline
  • Figure imgb1282
  • To a mixture of 4-bromo-1-fluoro-2-nitrobenzene (2.02 ml, 16.4 mmol) and 1,2,3,4-tetrahydroquinoline (8.72 g, 65.5 mmol), in a 100 mL pressure flask, was added K2CO3 (11.31 g, 82.0 mmol). The flask was sealed and the resulting mixture was heated at 130°C for 16 hours, before being cooled to rt, then partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted twice more with EtOAc. These organic extracts were combined with the original organic layer and were washed with brine, then dried over anhydrous sodium sulfate. The crude material was filtered, then concentrated in vacuo to afford a residue which was treated with 1-methylpiperazine (1.64 g, 16.4 mmol). The resultant mixture was heated at 80°C for one hour then cooled to room temperature. The crude reaction mixture was purified by flash chromatography to afford the title compound (1.43 g, 26%). MS(ES): m/z = 333 [M+H]+, HPLC Tr: 4.621.
    • B. 4'-(3,4-Dihydroquinolin-1(2H)-yl)-3'-nitro-[1,1'-biphenyl]-2-carbonitrile
  • Figure imgb1283
  • To a solution of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (1.43 g, 4.3 mmol) in dioxane (14.3 mL), in a sealable reaction vial, was added 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (1.20 g, 5.6 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.18 g, 0.22 mmol) and potassium phosphate, tribasic (2.24 g, 12.9 mmol). The mixture was purged with nitrogen for five minutes before the vial was sealed and the reaction heated at 100°C for two hours. The reaction was cooled to room temperature and the solids were removed by vacuum filtration through a fritted glass funnel. The filtrate was concentrate in vacuo and the crude reaction mixture was purified by flash chromatography to afford the title compound as a dark red solid (1.26 g, 83%). MS(ES): m/z = 356 [M+H]+, HPLC Tr: 4.401.
    • C. 1-(3-Nitro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroquinoline
  • Figure imgb1284
  • To a solution of 4'-(3,4-dihydroquinolin-1(2H)-yl)-3'-nitro-[1,1'-biphenyl]-2-carbonitrile (0.6 g, 1.7 mmol) in toluene (7 mL), in a sealable reaction vial, was added azidotributylstannane (3 ml, 10.9 mmol). The reaction was then heated at 105 °C for 16 hours before being cooled to room temperature. The solvent was removed under reduced pressure, and the resultant residue was purified by flash chromatography to afford the title compound (0.61 g, 86%). MS(ES): m/z = 399 [M+H]+, HPLC Tr: 4.071.
    • D. 4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-amine
  • Figure imgb1285
  • To a solution of ammonium chloride (0.49 g, 9.2 mmol) in water (0.92 mL) was added EtOH (6.4 mL). The mixture was cooled to 0 °C then treated with zinc (325 mesh flake, 0.83 g, 12.6 mmol). To this mixture was added a solution of 1-(3-nitro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroquinoline (0.61 g, 1.53 mmol) in EtOH (1 mL). The mixture was allowed to warm to room temperature and was stirred for 1.5 hours. After that time, the reaction mixture was filtered through a pad of Celite and the isolated solids were thoroughly rinsed with DCM. The combined filtrates were concentrated in vacuo to remove volatiles then partitioned between water and DCM. The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a brown residue. Purification by flash chromatography, followed by treatment with DCM, removal of remaining solids and concentration in vacuo afforded the title compound (0.21 g, 29%), which was used without further purification. MS(ES): m/z = 369 [M+H]+, HPLC Tr: 3.571.
    • E. 4-Nitrophenyl (4-(3,4-dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)carbamate
  • Figure imgb1286
  • To a homogeneous mixture of 4-(3,4-dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-amine (0.03 g, 0.08 mmol) in anhydrous THF (1.3 mL) was added 4-nitrophenyl carbonochloridate (0.02 g, 0.10 mmol). The mixture was stirred at room temperature for twenty minutes to afford 4-nitrophenyl (4-(3,4-dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)carbamate. MS(ES): m/z = 534 [M+H]+, HPLC Tr: 4.501. The entire reaction mixture was used without further purification.
    • 361. 1-(4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H -tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1287
  • To the reaction mixture from Step E, containing 4-nitrophenyl (4-(3,4-dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)carbamate, was added p-toluidine (12 mg, 0.11 mmol) followed by triethylamine (0.05 mL, 0.33 mmol). The mixture was then heated at 50 °C for thirty minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo then redissolved in DMF (1 mL) before beimg purified via via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 150 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (11.9 mg, 29% yield). MS(ES): m/z = 502 [M+H]+, HPLC Tr: 1.66j.
    • Example 362 1-(4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(6-methylpyridin-3 -yl)urea
  • Figure imgb1288
  • The title compound (25.2 mg, 60%) was prepared following a procedure analogous to that for the synthesis of Example 361, except that 6-methylpyridin-3-amine (12 mg, 0.11 mmol) was used instead of p-toluidine. MS(ES): m/z = 503 [M+H]+, HPLC Tr: 1.36j.
    • Example 363 1-(4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea
  • Figure imgb1289
  • The title compound (5.4 mg, 12%) was prepared following a procedure analogous to that for the synthesis of Example 361, except that 4-(trifluoromethoxy)aniline (20 mg, 0.11 mmol) was used instead of p-toluidine. MS(ES): m/z = 572 [M+H]+, HPLC Tr: 1.82j.
    • Example 364 1-(4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea
  • Figure imgb1290
  • The title compound (9.3 mg, 20%) was prepared following a procedure analogous to that for the synthesis of Example361, except that 2-fluoro-4-(trifluoromethyl)aniline (20 mg, 0.11 mmol) was used instead of p-toluidine. MS(ES): m/z = 574 [M+H]+, HPLC Tr: 1.86j.
    • Example 365 1-(4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(6-fluoropyridin-3 -yl)urea
  • Figure imgb1291
  • The title compound (24.7 mg, 59%) was prepared following a procedure analogous to that for the synthesis of Example361, except that 6-fluoropyridin-3-amine (13 mg, 0.11 mmol) was used instead of p-toluidine. MS(ES): m/z = 507 [M+H]+, HPLC Tr: 1.42j.
    • Example 366 1-(4-(3,4-Dihydroquinolin-1(2H)-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(3-methylisoxazol-5-yl)urea
  • Figure imgb1292
  • The title compound (11.5 mg, 26%) was prepared following a procedure analogous to that for the synthesis of Example361, except that 3-methylisoxazol-5-amine (11 mg, 0.11 mmol) was used instead of p-toluidine. MS(ES): m/z = 493 [M+H]+, HPLC Tr: 1.39j.
    • Example 367 (±)-1-(4-(3-Phenylpyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1293
    • A. (±)-1-(4-Bromo-2-nitrophenyl)-3-phenylpyrrolidine
  • Figure imgb1294
  • A mixture of 4-bromo-1-fluoro-2-nitrobenzene (0.39 ml, 3.2 mmol) and 3-phenylpyrrolidine (1.0 g, 6.79 mmol), in a sealable vial with pressure release cap, was heated at 105°C for 16 hours before being cooled to room temperature. The crude reaction mixture was purified by flash chromatography to afford the title compound (1.04 g, 94%). 1H NMR (400MHz, CDCl3) δ 7.90 (d, J=2.4 Hz, 1H), 7.46 (dd, J=9.2, 2.4 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.31 - 7.21 (m, 3H), 6.83 (d, J=9.2 Hz, 1H), 3.59 - 3.39 (m, 4H), 3.28 (ddd, J=10.1, 7.5, 2.9 Hz, 1H), 2.41 (dtd, J=12.1, 6.1, 2.6 Hz, 1H), 2.16 (dtd, J=2.0, 9.7, 7.7 Hz, 1H). MS(ES): m/z = 347 [M+H]+, HPLC Tr: 4.811.
    • 367. (±)-1(4-(3-Phenylpyrrolidin-1yl)-2'-(1-tetrazol-5-yl)-[1,1-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1295
  • The title compound (19.8 mg, 52%) was prepared following a procedure analogous to that for the synthesis of Example 361, except that (±)-1-(4-bromo-2-nitrophenyl)-3-phenylpyrrolidine was used instead of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline. MS(ES): m/z = 516 [M+H]+, HPLC Tr: 1.65j.
    • Example 368 (±)-1-(6-Methylpyridin-3-yl)-3-(4-(3-phenylpyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1296
  • The title compound (20.6 mg, 54%) was prepared following a procedure analogous to that for the synthesis of Example 362, except that (±)-1-(4-bromo-2-nitrophenyl)-3-phenylpyrrolidine was used instead of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline. MS(ES): m/z = 517 [M+H]+, HPLC Tr: 1.36j.
    • Example 369 (±)-1-(4-(3-Phenylpyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea
  • Figure imgb1297
  • The title compound (22.6 mg, 52%) was prepared following a procedure analogous to that for the synthesis of Example363, except that (±)-1-(4-bromo-2-nitrophenyl)-3-phenylpyrrolidine was used instead of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline. MS(ES): m/z = 586 [M+H]+, HPLC Tr: 1.79j.
    • Example 370 (±)-1-(2-Fluoro-4-(trifluoromethyl)phenyl)-3-(4-(3-phenylpyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1298
  • The title compound (9.5 mg, 22%) was prepared following a procedure analogous to that for the synthesis of Example 364, except that (±)-1-(4-bromo-2-nitrophenyl)-3-phenylpyrrolidine was used instead of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline. MS(ES): m/z = 588 [M+H]+, HPLC Tr: 1.85j.
    • Example 371 (±)-1-(6-Fluoropyridin-3-yl)-3-(4-(3-phenylpyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1299
  • The title compound (11.8 mg, 31%) was prepared following a procedure analogous to that for the synthesis of Example 365, except that (±)-1-(4-bromo-2-nitrophenyl)-3-phenylpyrrolidine was used instead of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline. MS(ES): m/z = 521 [M+H]+, HPLC Tr: 1.42j.
    • Example 372 (±)-1-(3-Methylisoxazol-5-yl)-3-(4-(3-phenylpyrrolidin-1-yl)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1300
  • The title compound (8.8 mg, 23%) was prepared following a procedure analogous to that for the synthesis of Example366, except that (±)-1-(4-bromo-2-nitrophenyl)-3-phenylpyrrolidine was used instead of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline. MS(ES): m/z = 507 [M+H]+, HPLC Tr: 1.38j.
    • Example 373 4'-(3,4-Dihydroquinolin-1(2H)-yl)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1301
    • A. 4'-(3,4-Dihydroquinolin-1(2H)-yl)-5-fluoro-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1302
  • To a solution of 1-(4-bromo-2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (0.40 g, 1.20 mmol) in DMF (10.5 mL), in a sealable reaction vial, was added 2-borono-4-fluorobenzoic acid (0.29 g, 1.57 mmol), K2CO3 (0.83 g, 6.02 mmol) and water (1.5 ml). The heterogenous mixture was purged with nitrogen for 15 minutes, before tetrakis(triphenylphophine)palladium(0) (0.07 g, 0.06 mmol) was added to the flask. The mixture was purged with nitrogen for an additional five minutes before the vial was sealed and the reaction heated at 100°C for three hours. The reaction mixture was cooled to room temperature before being treated with Et2O and water. Aqueous HCl (1N) was added until the aqueous layer reached pH 4. The mixture was thoroughly extracted with Et2O and these organic extracts were combined, washed with water then brine, and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated in vacuo to afford the crude product which was purified by flash chromatography to afford the title compound (0.34 g, 72%). MS(ES): m/z = 393 [M+H]+, HPLC Tr: 1.271.
    • 373. 4'-(3,4-Dihydroquinolin-1(2H)-yl)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1303
  • The title compound (11.8 mg, 41%) was prepared following a procedure analogous to that for the synthesis of Example 361, except that 4'-(3,4-dihydro-quinolin-1(2H)-yl)-5-fluoro-3'-nitro-[1,1'-biphenyl]-2-carboxylic acid was used instead of 1-(3-nitro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-1,2,3,4-tetrahydroquinoline. MS(ES): m/z = 496 [M+H]+, HPLC Tr: 1.67j.
  • Using the methods described herein, the following additional compounds of the invention were prepared.
    Example No. Compound HPLC Tr (M+H)+
    374
    Figure imgb1304
         		1.86j 590
    375
    Figure imgb1305
         		1.92j 596
    376
    Figure imgb1306
         		1.74j 527
    377
    Figure imgb1307
         		1.64j 491
    378
    Figure imgb1308
         		1.53j 502
    379
    Figure imgb1309
         		1.65j 526
    380
    Figure imgb1310
         		2.52j 540
    381
    Figure imgb1311
         		1.90j 546
    382
    Figure imgb1312
         		1.53j 537
    383
    Figure imgb1313
         		1.64j 561
    384
    Figure imgb1314
         		1.70j 565
    385
    Figure imgb1315
         		2.14j 539
    386
    Figure imgb1316
         		1.67j 534
    387
    Figure imgb1317
         		1.38j 535
    388
    Figure imgb1318
         		1.08j 523
    389
    Figure imgb1319
         		1.38j 522
    390
    Figure imgb1320
         		1.59j 594
    391
    Figure imgb1321
         		1.51j 486
    392
    Figure imgb1322
         		2.28j 608
    393
    Figure imgb1323
         		2.13j 581
    394
    Figure imgb1324
         		1.74j 537
    395
    Figure imgb1325
         		1.61j 499
    396
    Figure imgb1326
         		1.40j 489
    397
    Figure imgb1327
         		1.64j 506
    398
    Figure imgb1328
         		1.92j 543
    399
    Figure imgb1329
         		1.46j 519
    400
    Figure imgb1330
         		1.73j 563
    401
    Figure imgb1331
         		0.82j 506
    402
    Figure imgb1332
         		1.37j 524
    403
    Figure imgb1333
         		1.51j 574
    404
    Figure imgb1334
         		1.41j 562
    405
    Figure imgb1335
         		1.68j 556
    406
    Figure imgb1336
         		1.47j 556
    407
    Figure imgb1337
         		1.40j 544
    408
    Figure imgb1338
         		1.59j 509
    409
    Figure imgb1339
         		1.68j 558
    410
    Figure imgb1340
         		2.19j 548
    411
    Figure imgb1341
         		1.72j 559
    412
    Figure imgb1342
         		2.10j 578
    413
    Figure imgb1343
         		1.49j 550
    414
    Figure imgb1344
         		2.13v 654
    415
    Figure imgb1345
         		1.67j 572
    416
    Figure imgb1346
         		1.92j 554
    417
    Figure imgb1347
         		17.27a 550
    418
    Figure imgb1348
         		1.84j 526
    419
    Figure imgb1349
         		1.87j 544
    420
    Figure imgb1350
         		1.95j 544
    421
    Figure imgb1351
         		1.97k 562
    422
    Figure imgb1352
         		2.00k 572
    423
    Figure imgb1353
         		1.80j 568
    424
    Figure imgb1354
         		17.73a 502
    425
    Figure imgb1355
         		1.94j 492
    426
    Figure imgb1356
         		1.96j 510
    427
    Figure imgb1357
         		1.77j 530
    428
    Figure imgb1358
         		2.05j 548
    429
    Figure imgb1359
         		2.27k 516
    430
    Figure imgb1360
         		1.66j 546
    431
    Figure imgb1361
         		1.71j 540
    432
    Figure imgb1362
         		1.69j 522
    433
    Figure imgb1363
         		2.00j 542
    434
    Figure imgb1364
         		2.12j 574
    435
    Figure imgb1365
         		2.06j 536
    436
    Figure imgb1366
         		2.08j 580
    437
    Figure imgb1367
         		2.03j 518
    438
    Figure imgb1368
         		2.10j 556
    439
    Figure imgb1369
         		1.67j 506
    440
    Figure imgb1370
         		1.72j 526
    441
    Figure imgb1371
         		1.73j 550
    442
    Figure imgb1372
         		174j 544
    443
    Figure imgb1373
         		1.66j 488
    444
    Figure imgb1374
         		1.65j 512
    445
    Figure imgb1375
         		1.69j 502
    446
    Figure imgb1376
         		1.51j 526
    447
    Figure imgb1377
         		1.51j 520
    448
    Figure imgb1378
         		1.91j 492
    449
    Figure imgb1379
         		1.93j 516
    450
    Figure imgb1380
         		1.93j 510
    451
    Figure imgb1381
         		1.89j 558
    452
    Figure imgb1382
         		1.90j 564
    453
    Figure imgb1383
         		1.92j 550
    454
    Figure imgb1384
         		1.93j 528
    455
    Figure imgb1385
         		1.60k 526
    456
    Figure imgb1386
         		4.561 540
    457
    Figure imgb1387
         		1.75j 523
    458
    Figure imgb1388
         		2.08j 524
    459
    Figure imgb1389
         		2.05j 512
    460
    Figure imgb1390
         		1.93j 498
    461
    Figure imgb1391
         		1.95j 516
    462
    Figure imgb1392
         		1.95j 522
    463
    Figure imgb1393
         		1.89j 527
    464
    Figure imgb1394
         		1.88j 476
    465
    Figure imgb1395
         		1.90j 528
    466
    Figure imgb1396
         		1.92j 522
    467
    Figure imgb1397
         		17.73a 578
    468
    Figure imgb1398
         		2.11j 592
    469
    Figure imgb1399
         		2.05j 586
    470
    Figure imgb1400
         		1.97j 590
    471
    Figure imgb1401
         		4.531 498
    472
    Figure imgb1402
         		4.451 522
    473
    Figure imgb1403
         		4.681 516
    474
    Figure imgb1404
         		4.641 500
    475
    Figure imgb1405
         		4.581 524
    476
    Figure imgb1406
         		4.801 518
    477
    Figure imgb1407
         		2.78q 496
    478
    Figure imgb1408
         		2.67q 478
    479
    Figure imgb1409
         		2.73q 530
    480
    Figure imgb1410
         		2.68q 512
    481
    Figure imgb1411
         		2.36k 508
    482
    Figure imgb1412
         		4.811 606
    483
    Figure imgb1413
         		4.751 516
    484
    Figure imgb1414
         		4.641 520
    485
    Figure imgb1415
         		1.64w 606
    486
    Figure imgb1416
         		1.26w 524
    487
    Figure imgb1417
         		4.21x 559
    488
    Figure imgb1418
         		4.75x 530
    489
    Figure imgb1419
         		4.38x 510
    491
    Figure imgb1420
         		1.18y 518
    492
    Figure imgb1421
         		2.15k 508
    493
    Figure imgb1422
         		2.24k 508
    494
    Figure imgb1423
         		1.09y 542
    495
    Figure imgb1424
         		4.97x 558
    496
    Figure imgb1425
         		5.17x 596
    497
    Figure imgb1426
         		2.02k 504
    498
    Figure imgb1427
         		1.93k 516
    499
    Figure imgb1428
         		1.26w 516
    500
    Figure imgb1429
         		4.81x 542
    501
    Figure imgb1430
         		4.90x 570
    • Example 502 1-(4-((4-fluoro-2-(trifluoromethyl)benzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1431
    • 502A. 3,3,3-Trifluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)propanamide
  • Figure imgb1432
  • The title compound was prepared from 3,3,3-trifluoropropanoic acid and (4-fluoro-2-(trifluoromethyl)phenyl)-methanamine by the general procedure used for the synthesis of Example 651A. MS(ES): m/z = 304.32 [M+H]+.
    • 502B. 3,3,3-Trifluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)propan-1-amine
  • Figure imgb1433
  • The title compound was prepared from 3,3,3-trifluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)propanamide by the general procedure used for the synthesis of Example 651B. MS(ES): m/z = 290 [M+H]+.
    • 502C. 4-Bromo-N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • Figure imgb1434
  • To a solution of 3,3,3-trifluoro-N-(4-fluoro-2-(trifluoromethyl)benzyl)propan-1-amine (631 mg, 2.182 mmol) in tetrahydrofuran (4 mL) was added LiHMDS (5.45 mL, 5.45 mmol, 1 M) at -78 °C. The mixture stirred for 10 min, then 4-bromo-1-fluoro-2-nitrobenzene was added (400 mg, 1.818 mmol). After 3h TLC suggested the complete consumption of starting material. The reaction mixture was poured into cooled saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel (230-400 mesh) column chromatography using ethyl acetate and hexane. The solvent was evaporated to get 4-bromo-N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline (550 mg, 47.0% yield) as a yellow liquid. MS(ES): m/z = 489 [M+H]+.
    • 502D. 4-Bromo-Nl-(4-fluoro-2-(trifluoromethyl)benzyl)-Nl-(3,3,3-trifluoropropyl)benzene-1,2-diamine g
  • The title compound was prepared from 4-bromo-N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline at 0°C by the general procedure used for the conversion of 1A to 1B. MS(ES): m/z = 461.14 [M+H]+.
    • 502E. N4-(4-Fluoro-2-(trifluoromethyl)benzyl)-2'-(1H-tetrazol-5-yl)-N4-(3,3,3-trifluoropropyl)-[1,1'-biphenyl]-3,4-diamine
  • Figure imgb1435
  • The title compound was prepared from 4-bromo-N1-(4-fluoro-2-(trifluoromethyl)benzyl)-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine by the general procedure used for the synthesis of Example 651 MS(ES): m/z = 525 [M+H]+.
    • 502. 1-(4-((4-Fluoro-2-(trifluoromethyl)benzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1436
  • To the stirred solution of N4-(4-fluoro-2-(trifluoromethyl)benzyl)-2'-(1H-tetrazol-5-yl)-N4-(3,3,3-trifluoropropyl)-[1,1'-biphenyl]-3,4-diamine (20 mg, 0.038 mmol) in methylene chloride (200 µL) was added 1-isocyanato-4-methylbenzene (5.08 mg, 0.038 mmol). The reaction was stirred overnight. The solvent was evaporated and the crude sample was purified by RP-HPLC (acetonitrile-water gradient + TFA). The product containing fraction was partially evaporated to remove the acetonitrile and then lyophilized to give the product (15 mg). MS(ES): m/z = 656 [M+H]+ HPLC Tr: 22.46u.
    • Example 503 1-(2'-(1H-Tetrazol-5-yl)-4-((4-(trifluoromethoxy)benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea
  • Figure imgb1437
  • Example 503 was prepared using the procedures used to make Example 503. MS(ES): m/z = 724 [M+H]+, HPLC Tr: 23.63u.
    • Example 504 1-(2'-(1H-Tetrazol-5-yl)-4-((4-(trifluoromethoxy)benzyl)(3,3,3-trifluoropropyl)amino)-[1,1'-biphenyl]-3-yl)-3-(2,4-difluorophenyl)urea
  • Figure imgb1438
  • Example 504 was prepared using the procedures used to make Example 503. MS(ES): m/z = 676 [M+H]+, HPLC Tr: 22.63u
    • Example 505 1-(4-((2,4-Dichlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1439
    • 505A. N-(2,4-Dichlorobenzyl)-3,3,3-trifluoropropanamide
  • Figure imgb1440
  • To a stirred solution of (2,4-dichlorophenyl)methanamine (2.0 g, 11.36 mmol), 3,3,3-trifluoropropanoic acid (1.74 g, 13.63 mmol) and pyridine (1.79 g, 22.72 mmol), in methylene chloride was added phosphorus oxychloride (1.27 mL, 13.63 mmol) at 0 °C. The reaction mixture was brought to room temperature and stirred for 1 h. The reaction mixture was diluted with methylene chloride and washed with water then brine solution.The organic layer was dried over sodium sulfate, filtered and concentrated to provided N-(2,4-dichlorobenzyl)-3,3,3-trifluoropropanamide (2.93 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.40 (d, 1H, J = 2.0 Hz), 7.32 (d, 1H, J = 14.4 Hz), 7.24 (dd, 1H, J = 8.4, 2.0 Hz), 6.17 (brs, 1H), 4.53 (d, 2H, J = 6.0 Hz), 3.06-3.14 (q, 2H).
    • 505B. N-(2,4-Dichlorobenzyl)-3,3,3-trifluoropropan-1-amine
  • Figure imgb1441
  • To a stirred solution of N-(2,4-dichlorobenzyl)-3,3,3-trifluoropropanamide (2.9 g, 10.14 mmol) in tetrahydrofuran (150 mL) was added borane-methyl sulfide complex (4.81 mL, 50.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to 0 °C, quenched with methanol slowly (effervescence observed), then excess solvent was removed completely under reduced pressur. Methanol was added at 0 °C and the mixture refluxed overnight. The methanol was removed and 1.5 N hydrochloric acid was added. The mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated to provide N-(2,4-dichlorobenzyl)-3,3,3-trifluoropropan-1-amine (2.25 g, 8.27 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (d, 1H, J = 8.4 Hz), 7.32 (d, 1H, J = 14.4 Hz), 7.24 (dd, 1H, J = 8.4, 2.0 Hz), 4.22 (d, 2H, J = 8.4 Hz), 3.08-3.11 (q, 2H), 2.78-2.84 (q, 2H).
    • 505C. 4-Bromo-N-(2,4-dichlorobenzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline
  • Figure imgb1442
  • A pressure tube was charged with 4-bromo-1-fluoro-2-nitrobenzene (1.5 g, 6.82 mmol), N-(2,4-dichlorobenzyl)-3,3,3-trifluoropropan-1-amine (2.22 g, 8.18 mmol), DIPEA (2.38 mL, 13.64 mmol), in NMP (10.5 mL) solvent. The reaction mixture was heated at 130 °C for 72 hours. The reaction mixture was cooled to room temperature, diluted with MTBE, washed with water (3x), brine (1x). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a crude dark brown solid. Purification using flash column chromatography (0% to 5% ethyl acetate/hexane gradient) provided 4-bromo-N-(2,4-dichlorobenzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline (0.750 g).
    • 505D. 4-Bromo-N1-(2,4-dichlorobenzyl)-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine
  • Figure imgb1443
  • The title compound was prepared from 4-bromo-N-(2,4-dichlorobenzyl)-2-nitro-N-(3,3,3-trifluoropropyl)aniline by the general procedure used for forming 1B. MS(ES): m/z = 443.0 [M+H]+.
    • 505E. N4-(2,4-Dichlorobenzyl)-2'-(1H-tetrazol-5-yl)-N4-(3,3,3-trifluoropropyl)biphenyl -3,4-diamine
  • Figure imgb1444
  • To a stirred solution of 4-bromo-N1-(2,4-dichlorobenzyl)-N1-(3,3,3-trifluoropropyl)benzene-1,2-diamine (140 mg, 0.317 mmol), potassium carbonate 2M solution (3.33 mL, 6.65 mmol), in dioxane ethanol mixture was added (2-(1H-tetrazol-5-yl)phenyl)boronic acid (60 mg, 0.317 mmol). The reaction mixture was degassed for 30 minutes. Pd(Ph3P)4 (18 mg, 0.016 mmol) was added and the reaction was again degassed for 5 minutes then heated at 85 °C for 3 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with water, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification using flash chromatography provided (80 mg). 1H NMR (400 MHz, CDCl3) δ ppm 7.63-7.67 (m, 2H), 7.51-7.56 (m, 2H), 7.44 (d, 1H, J = 2.0 Hz), 7.27 (dd, 1H, J = 8.0, 2.0 Hz), 7.17 (d, 1H, J = 8.4 Hz), 7.01 (d, 1H, J = 8.0 Hz), 6.61 (d, 1H, J = 2.0 Hz), 6.34 (dd, 1H, J = 8.0, 2.0 Hz), 4.20 (s, 2H), 3.24 (t, 2H), 2.31-2.38 (m, 2H). MS(ES): m/z = 507 [M+H]+.
    • 505. 1-(4-((2,4-Dichlorobenzyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1445
  • To the stirred solution of N4-(4-fluoro-2-(trifluoromethyl)benzyl)-2'-(1H-tetrazol-5-yl)-N4-(3,3,3-trifluoropropyl)-[1,1'-biphenyl]-3,4-diamine (20 mg, 0.038 mmol) in methylene chloride (200 µL) was added 1-isocyanato-4-methylbenzene (5.08 mg, 0.038 mmol). The reaction was stirred overnight. The solvent was evaporated and the crude sample was purified by RP-HPLC (acetonitrile-water gradient + TFA). The product containing fraction was partially evaporated to remove the acetonitrile and then lyophilized to give the product (20 mg). MS(ES): m/z = 640 [M+H]+ HPLC Tr: 23.54u,.
    • Example 506 1-(4-((pyridin-2-ylmethyl)(3,3,3-trifluoropropyl)amino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1446
  • Example 506 was prepared using the procedures described for Example 505. MS(ES): m/z = 573 [M+H]+, HPLC Tr: 14.4u.
    • Example 507 4'-(Cyclohexyl(isobutyl)amino)-3'-(3-(3, 5-dibromo-4-methylphenyl)ureido)-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1447
    • 507A. Methyl 3'-amino-4'-(cyclohexyl(isobutyl)amino)-5-fluoro-[1,r-biphenyl]-2-carboxylate
  • Figure imgb1448
  • To a stirred solution of 4-bromo-N1-cyclohexyl-N1-isobutylbenzene-1,2-diamine (200 mg, 0.615 mmol)(Intermediate iiiz in Table 1A) in dry dioxane (4.0 ml) added methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (207 mg, 0.738 mmol), followed by potassium phosphate (0.153 ml, 1.845 mmol).The reaction was purged with argon for 15 minutes and PdCl2(dppf) (90 mg, 0.123 mmol) was added. The reaction was again purged with argon for 5 minutes. The reaction was then sealed and heated to 80°C overnight. The reaction was diluted with ethyl acetate (10 ml) and washed sequentially with water(10 ml) and brine(10 ml). The organic phase was dried over sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column using 60-120 mesh silica gel using 0-20% ethyl acetate/petroleum ether as eluent. Evaporation of the appropriate fractions provided the product as a semi-solid.
    • 507B. Ethyl 4'-(cyclohexyl(isobutyl)amino)-3'-(3-(3,5-dibromo-4-methylphenyl)ureido)-5-fluoro-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1449
  • To a stirred solution of 3,5-dibromo-4-methylaniline (0.020 g, 0.075 mmol) in dry methylene chloride (2.0 mL) under nitrogen was added sodium carbonate (0.040 g, 0.377 mmol). The reaction was cooled to 0°C and phosgene (0.037 g, 0.075 mmol) solution was added. The reaction was stirred at room temperature for 1.5 hour. The reaction was filtered through celite, washed with dry methylene chloride (2 ml) and concentrated under reduced pressure. After pumping down under high vacuum the product 1,3-dibromo-5-isocyanato-2-methylbenzene (20 mg, 0.069 mmol, 91 % yield) was obtained.
    This intermediate 1,3-dibromo-5-isocyanato-2-methylbenzene (0.02 g, 0.069 mmol) was dissolved in dry methylene chloride (1.0 ml) and methyl 3'-amino-4'-(cyclohexyl(isobutyl)amino)-5-fluoro-[1,1'-biphenyl]-2-carboxylate (0.027 g, 0.069 mmol)(dissolved in methylene chloride (2 ml)) was added. The reaction was stirred for 30 minutes when the mixture was concentrated to give the crude product. The crude product was purified by preparative TLC using 10% ethyl acetate in petroleum ether as eluent. The pure product band was extracted with methylene chloride and filtered through a celite bed. Evaporation then gave the pure product (22 mg).
    • 507. 4'-(Cyclohexyl(isobutyl)amino)-3'-(3-(3,5-dibromo-4-methylphenyl)ureido)-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1450
  • To a stirred solution of methyl 4'-(cyclohexyl(isobutyl)amino)-3'-(3-(3,5-dibromo-4-methylphenyl)ureido)-5-fluoro-[1,1'-biphenyl]-2-carboxylate (0.02 g, 0.029 mmol), in a mixture of dry tetrahydrofuran (1.0 mL), methanol (1.0 mL), and water (0.200 mL) cooled to 0°C was added lithium hydroxide monohydrate (6.09 mg, 0.145 mmol). The reaction was stirred at room temperature for 36 hours. Reaction mixture was concentrated to give an off white solid, The reaction was diluted with MTBE and washed with water. Aqueous layer was extracted with MTBE (2X10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give an off white solid. The crude product was purified by preparative HPLC to give the final product (10 mg). MS(ES): m/z = 676 [M+H]+ HPLC Tr: 27.32u.
    • Example 509 1-(4-(Dicyclopropylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(5-methylisoxazol-3-yl)urea
  • Figure imgb1451
    • 509A. 4-Bromo-N,N-dicyclopropyl-2-nitroaniline
  • Figure imgb1452
  • To a homogeneous mixture of 4-bromo-1-fluoro-2-nitrobenzene (700 mg, 3.18 mmol) in N-methylpyrrolidinone (3.2 mL) in a sealable tube, was added DIPEA (2.2 mL, 12.60 mmol) followed by dicyclopropylamine hydrochloride (510 mg, 3.82 mmol). The tube was sealed and the mixture was heated to 110°C. The reaction was heated for 3 hours when it was cooled. The reaction was quenched with water then extracted with three portions of ethyl acetate. The combined organic layers were washed with brine then dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a blood red oil (1.3035g). The crude product was purified on an Isco CombiFlash System using a 40 g silica gel column. The compound was eluted with 0-50% ethyl acetate in hexanes. As the separation was not good, the chromatography was repeated; however, adequate separation did not occur on this attempt either. Evaporation of the product containing fractions in vacuo afforded an amber oil (609.8 mg). This material still contains significant impurities but, as purification is problematic, the compound is carried forward into the next reaction.
    • 509B. 4-Bromo-N1,N1-dicyclopropylbenzene-1,2-diamine
  • Figure imgb1453
  • To a solution of 4-bromo-N,N-dicyclopropyl-2-nitroaniline (609.8 mg, 2.052 mmol) in ethanol (15 mL) and water (3.00 mL), under nitrogen, was added ammonium chloride (2195 mg, 41.0 mmol). The reaction was stirred for 5 minutes before adding zinc (2683 mg, 41.0 mmol). The mixture was stirred at room temperature for ca. 6 hours. The reaction mixture was filtered through a pad of Celite which was then thoroughly rinsed with chloroform. The combined organic filtrates were concentrated in vacuo to afford a dark brown residue which was redissolved in chloroform. The crude product was purified on Isco CombiFlash System using a 40 g silica flash column. The compound was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a golden oil (180 mg). 1H NMR (400MHz, DMSO-d6) δ 7.09 (d, J=8.4 Hz, 1H), 6.77 (d, J=2.2 Hz, 1H), 6.64 (dd, J=8.3, 2.3 Hz, 1H), 4.93 (s, 2H), 0.48 - 0.34 (m, 8H) (cyclopropyl methines are obscured by DMSO).
    • 509C. N4,N4-Dicyclopropyl-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine
  • Figure imgb1454
  • To a stirred solution of 4-bromo-N1,N1-dicyclopropylbenzene-1,2-diamine (45 mg, 0.168 mmol) in argon-purged dimethylformamide (1 mL) was added 2-(tetrazol-5-yl)phenylboronic acid (64.0 mg, 0.337 mmol), followed by cesium carbonate (0.561 mL, 0.842 mmol, 1.5 M aqueous). The reaction was purged with argon for 15 minutes then Pd(Ph3P)4 (19.46 mg, 0.017 mmol) was added. The reaction was purged with argon for another 5 minutes when the vial was capped and heated to 100°C. The reaction was heated for 4.5 hours and then allowed to cool to room temperature overnight. The crude product was purified on an Isco CombiFlash System using a RediSep normal phase silica flash column (12g). The compound was eluted with a 0-100% ethyl acetate in hexanes gradient. Evaporation of the product containing fractions gave the desired product as a gold residue (15.5 mg). MS(ES): m/z = 333 [M+H]+.
    • 509. 1-(4-(Dicyclopropylamino)-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(5-methylisoxazol-3 -yl)urea
  • Figure imgb1455
  • To a solution of 5-methylisoxazol-3-amine (11 mg, 0.112 mmol) in anhydrous tetrahydrofuran (1 mL), at room temperature in a sealable vial, was added 4-nitrophenyl chloroformate (27.1 mg, 0.135 mmol). The mixture was stirred for 0.5 hour when LCMS indicated the presence of the desired carbamate intermediate. The reaction was divided in half by volume and one portion was used in this preparation. This material was added to a solution of N4,N4-dicyclopropyl-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3,4-diamine (15.5 mg, 0.047 mmol) in methylene chloride (2 mL) in a sealable vial. Triethylamine (0.01 mL, 0.072 mmol) was then added and the reaction stirred for 10 days. The reaction was concentrated to dryness then redissolved in 1.5mL dimethylformamide. The reaction was filtered through an Acrodisc (13mm syringe filter with 0.45µm Nylon membrane) syringe filter. The crude material was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 100 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-100% B over 10 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 0.6 mg. MS(ES): m/z = 457 [M+H]+, HPLC Tr: 1.85k.
    • Example 510 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-3'-(3-(2-fluorophenyl)ureido)-[1,r-biphenyl]-2-carboxylic acid
  • Figure imgb1456
  • Example 510 was prepared using the procedures used to make Example 532. 1H NMR (500MHz, METHANOL-d4) δ 8.06 (d, J=2.0 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.38 (td, J=7.4, 1.5 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.16 - 7.07 (m, 3H), 7.06 (dd, J=7.9, 2.0 Hz, 1H), 2.82 (br. s., 3H), 2.12 - 2.02 (m, 2H), 1.88 (br. s., 2H), 1.79 - 1.60 (m, 4H), 1.51 (dquin, J=13.3, 6.7 Hz, 1H), 0.86 (d, J=6.9 Hz, 6H). MS(ES): m/z = 539 [M+H]+, HPLC Tr: 2.18k.
    • Example 511 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-3'-(3-(4-(trifluoromethoxy)phenyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1457
  • Example 511 was prepared using the procedures used to make Example 532. MS(ES): m/z = 606 [M+H]+ HPLC Tr: 2.39k, 1H NMR (500MHz, METHANOL-d4) δ 8.13 (d, J=2.0 Hz, 1H), 7.52 (d, J=9.4 Hz, 2H), 7.45 (d, J=4.0 Hz, 3H), 7.36 (dq, J=8.2, 4.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 2.83 (br. s., 3H), 2.05 (d, J=6.4 Hz, 2H), 1.98 - 1.89 (m, 2H), 1.79 - 1.58 (m, 4H), 1.50 (dquin, J=13.3, 6.7 Hz, 1H), 0.87 (d, J=6.4 Hz, 6H).
    • Example 512 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1458
  • Example 512 was prepared using the procedures used to make Example 532. MS(ES): m/z = 536 [M+H]+ HPLC Tr: 2.25k, 1H NMR (500MHz, METHANOL-d4) δ 8.16 (d, J=2.0 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.54 - 7.49 (m, 1H), 7.48 - 7.44 (m, 1H), 7.38 (td, J=7.6, 1.2 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.19 - 7.10 (m, 3H), 6.99 (dd, J=7.9, 2.0 Hz, 1H), 2.82 - 2.68 (m, 3H), 2.32 (s, 3H), 2.08 - 1.98 (m, 2H), 1.83 - 1.53 (m, 6H), 1.51 - 1.42 (m, 1H), 0.82 (d, J=6.4 Hz, 6H).
    • Example 513 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-3'-(3-(4-(trifluoromethyl)phenyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1459
  • Example 513 was prepared using the procedures used to make Example 532. MS(ES): m/z = 590 [M+H]+ HPLC Tr: 2.38k. 1H NMR (500MHz, METHANOL-d4) δ 8.12 (d, J=2.0 Hz, 1H), 7.67 (d, J=7.4 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.54 (d, J=8.9 Hz, 2H), 7.44 (d, J=4.0 Hz, 2H), 7.38 - 7.30 (m, 1H), 7.22 - 7.17 (m, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 2.84 (br. s., 3H), 2.13 - 2.02 (m, 2H), 1.96 (d, J=8.9 Hz, 2H), 1.78 - 1.60 (m, 4H), 1.51 (dquin, J=13.3, 6.6 Hz, 1H), 0.88 (d, J=6.9 Hz, 6H).
    • Example 514 1-(4-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2'-(1H-tetrazol-5-yl)-[1,r-biphenyl]-3-yl)-3-(4-(trifluoromethoxy)phenyl)urea
  • Figure imgb1460
  • Example 514 was prepared using the procedures used to make Example 531. MS(ES): m/z = 630 [M+H]+ HPLC Tr: 2.35k. 1H NMR (500MHz, METHANOL-d4) δ 7.95 (d, J=2.0 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.57 (d, J=4.0 Hz, 2H), 7.52 (d, J=8.9 Hz, 2H), 7.50 - 7.45 (m, 1H), 7.17 (d, J=8.9 Hz, 2H), 6.99 (d, J=7.9 Hz, 1H), 6.55 (dd, J=7.9, 2.0 Hz, 1H), 2.77 (d, J=6.9 Hz, 3H), 2.05 (br. s., 2H), 1.86 (br. s., 2H), 1.77 - 1.57 (m, 4H), 1.43 (dquin, J=13.3, 6.6 Hz, 1H), 0.84 (d, J=6.9 Hz, 6H).
    • Example 515 4'-(Cyclohexyl(isobutyl)amino)-2',5-difluoro-5'-(3-(l-methyl-1H-pyrazol-3-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1461
  • Example 515 was prepared using the methology described for Example 522. MS(ES): m/z = 526 [M+H]+ HPLC Tr: 1.79k. 1H NMR (500MHz, DMSO-d6) δ 13.86 - 11.94 (m, 1H), 9.65 (br. s., 1H), 8.08 (d, J=8.4 Hz, 1H), 7.91 (dd, J=8.9, 5.9 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.34 (td, J=8.4, 2.5 Hz, 1H), 7.26 (dd, J=9.7, 2.7 Hz, 1H), 7.07 (d, J=11.9 Hz, 1H), 6.02 (br. s., 1H), 3.74 (s, 3H), 2.82 (br. s., 2H), 2.69 - 2.58 (m, 1H), 1.88 (d, J=11.4 Hz, 2H), 1.69 (d, J=11.9 Hz, 2H), 1.53 (d, J=10.9 Hz, 1H), 1.41 (dquin, J=13.3, 6.7 Hz, 1H), 1.35 - 1.20 (m, 2H), 1.16 - 0.97 (m, 3H), 0.87 (d, J=6.4 Hz, 6H).
    • Example 516 4'-(Cyclohexyl(isobutyl)amino)-2',5-difluoro-5'-(3-(m-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1462
  • Example 516 was prepared using the methology described for Example 522. MS(ES): m/z = 536 [M+H]+ HPLC Tr: 2.06k. 1H NMR (500MHz, METHANOL-d4) δ 8.02 - 7.96 (m, 2H), 7.26 (s, 1H), 7.21 - 7.16 (m, 3H), 7.12 (td, J=8.2, 2.5 Hz, 1H), 6.92 (d, J=5.9 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 2.76 (d, J=6.9 Hz, 2H), 2.60 (t, J=11.6 Hz, 1H), 2.33 (s, 3H), 1.73 (d, J=9.9 Hz, 4H), 1.58 (d, J=11.9 Hz, 1H), 1.51 (dquin, J=13.3, 6.7 Hz, 1H), 1.35 - 1.21 (m, 2H), 1.21 - 0.99 (m, 3H), 0.84 (d, J=6.4 Hz, 6H).
    • Example 517 4'-(Cyclohexyl(isobutyl)amino)-2',5-difluoro-5'-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1463
  • Example 517 was prepared using the methology described for Example 522. MS(ES): m/z = 591 [M+H]+ HPLC Tr: 2.06k. 1H NMR (500MHz, METHANOL-d4) δ 8.64 (d, J=2.5 Hz, 1H), 8.34 (dd, J=8.7, 2.2 Hz, 1H), 8.03 - 7.95 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.18 (dd, J=9.4, 3.0 Hz, 1H), 7.13 (td, J=8.3, 2.7 Hz, 1H), 6.92 (d, J=11.4 Hz, 1H), 2.84 (d, J=6.9 Hz, 2H), 2.75 - 2.65 (m, 1H), 1.93 (d, J=11.4 Hz, 2H), 1.78 (d, J=12.9 Hz, 2H), 1.60 (d, J=11.9 Hz, 1H), 1.58 - 1.49 (m, 1H), 1.44 - 1.33 (m, 2H), 1.28 - 1.04 (m, 4H), 0.90 (d, J=6.4 Hz, 6H).
    • Example 518 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(5-methylisoxazol-3-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1464
    • 518A. N-(4,4-difluorocyclohexyl)isobutyramide
  • Figure imgb1465
  • A solution of 4,4-difluorocyclohexanamine hydrochloride (426.3 mg, 2.484 mmol) in anhydrous methylene chloride (15 mL) was cooled to 0 °C under nitrogen. Triethylamine (0.74 mL, 5.31 mmol) was then added. The mixture was stirred at 0 °C for 15 minutes when isobutyryl chloride (0.25 mL, 2.386 mmol) was added dropwise via syringe. The mixture was stirred and allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution then extracted with four portions of methylene chloride. The combined organic extracts were washed with 1N hydrochloric acid and brine. This organic phase was dried over sodium sulfate. LCMS of acidic aqueous layer suggests presence of product. Extract with three portions of 5% MeOH/CHC13. HPLC of the aqueous layer showed no further product and was discarded. The methanol-chloroform extract was washed with brine and the organic layer was added to the original methylene chloride extract. The combined extracts were dried over sodium sulfate, filtered and evaporated to afford a white solid (513.9 mg). 1H NMR (400MHz, CHLOROFORM-d) δ 5.46 - 5.23 (m, 1H), 4.03 - 3.78 (m, 1H), 2.43 - 2.26 (m, 1H), 2.22 - 1.98 (m, 4H), 1.98 - 1.73 (m, 2H), 1.59 - 1.45 (m, 2H), 1.18 (d, J=7.0 Hz, 6H).
    • 518B. 4,4-Difluoro-N-isobutylcyclohexanamine
  • Figure imgb1466
  • To a solution of N-(4,4-difluorocyclohexyl)isobutyramide (510 mg, 2.485 mmol) in anhydrous THF (15 mL), at room temperature under nitrogen, was added borane-THF complex (6 mL, 6.00 mmol, 1M solution in THF) via syringe. Stirring was continued overnight. The reaction carefully quenched with methanol before being concentrated in vacuo to afford an off-white residue (491.9 mg). This material was used in the subsequent transformation without purification.
    • 518C. 4-Bromo-N-(4,4-difluorocyclohexyl)-5-fluoro-N-isobutyl-2-nitroaniline
  • Figure imgb1467
  • To a solution of 5-bromo-2,4-difluoronitrobenzene (537 mg, 2.258 mmol) in anhydrous. NMP (1 mL), under nitrogen, was added DIPEA (1.183 mL, 6.77 mmol) followed by 4,4-difluoro-N-isobutylcyclohexanamine (475 mg, 2.484 mmol) in NMP (2 mL). The mixture was warmed to 110 °C and stirred for three days. The reaction was cooled to room temperature and diluted with ether. The diluted reaction was washed twice with 1N hydrochloric acid. The organic layer was then washed twice with a saturated solution of sodium bicarbonate and then brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark brown residue (925.2mg). The crude product was purified on an Isco CombiFlash System using a 24 g silica column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a red-orange solid (682 mg). 1H NMR (400MHz, CHLOROFORM-d) δ 8.04 (d, J=7.3 Hz, 1H), 6.95 (d, J=10.8 Hz, 1H), 3.13 - 2.95 (m, 1H), 2.87 (d, J=7.3 Hz, 2H), 2.16 (dd, J=11.0, 3.3 Hz, 2H), 1.99 - 1.75 (m, 5H), 1.75 - 1.63 (m, 2H), 0.92 (d, J=6.6 Hz, 6H). MS(ES): m/z = 409 [M+H]+.
    • 518D. 4-Bromo-N1-(4,4-difluorocyclohexyl)-5-fluoro-N1-isobutylbenzene-1,2-diamine
  • Figure imgb1468
  • A solution of 4-bromo-N-(4,4-difluorocyclohexyl)-5-fluoro-N-isobutyl-2-nitroaniline (680 mg, 1.662 mmol) in ethanol (6 mL) and water (1.200 mL) was cooled to 0°C under nitrogen. The reaction was treated with zinc(652 mg, 9.97 mmol) and ammonium chloride (533 mg, 9.97 mmol). The reaction was then stirred overnight. The reaction mixture was then filtered through a pad of Celite which was then thoroughly rinsed with chloroform. The combined organic filtrates were concentrated in vacuo to afford a dark residue which was partitioned between ethyl acetate and water. The layers were separated and the organic layer was concentrated in vacuo to afford a dark purple oily residue (722.0 mg). The crude product was purified on an Isco CombiFlash System using a 40 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a purple oil (308 mg). 1H NMR (400MHz, DMSO-d6) δ 7.06 (d, J=10.6 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 4.89 (s, 2H), 2.95 - 2.64 (m, 3H), 1.91 - 1.68 (m, 4H), 1.58 (d, J=11.4 Hz, 2H), 1.36 (dquin, J=13.4, 6.7 Hz, 1H), 0.81 (d, J=6.6 Hz, 6H). MS(ES): m/z = 379 [M+H]+.
    • 518E. Methyl 5'-amino-4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1469
  • To a stirred solution of 4-bromo-N1-(4,4-difluorocyclohexyl)-5-fluoro-N1-isobutylbenzene-1,2-diamine (305 mg, 0.804 mmol) in dry dioxane (5mL) was added methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (270 mg, 0.965 mmol) and potassium phosphate (512 mg, 2.413 mmol). The reaction was purged with argon for 15 minutes and then PdCl2(dppf) (118 mg, 0.161 mmol) was added. The reaction was purged with argon for another 5 minutes. The reaction was sealed and heated to 80°C overnight. The cooled reaction mixture was concentrated in vacuo to remove volatiles before being redissolved in ethyl acetate. The mixture was washed sequentially with water, then brine, before being dried over sodium sulfate, filtered and evaporated to afford a dark brown oil (928.9 mg). The crude product was purified on an Isco CombiFlash System using a 40 g silica gel column. The product was eluted with a gradient of 0-50% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as an oil (224.3 mg). MS(ES): m/z = 453 [M+H]+.
    • 518. 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(5-methylisoxazol-3-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1470
  • A reaction vial was charged with methyl 5'-amino-4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylate (37 mg, 0.082 mmol) in anhydrous tetrahydrofuran (2 mL). 4-Nitrophenyl chloroformate (18.13 mg, 0.090 mmol) was added followed by triethylamine (0.23 mL, 1.650 mmol). After 40 minutes, 5-methylisoxazol-3-amine (64.2 mg, 0.654 mmol) was added and the reaction warmed to 50°C. The reaction was stirred overnight. LCMS suggests partial conversion to product. The reaction was quenched with water and then extracted twice with ethyl acetate. The combined organic extracts were washed with brine and then concentrated in vacuo to afford a gold-yellow residue. This material was resubjected to the reaction conditions. The cooled reaction was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo to afford a yellow residue (49 mg). LCMS is consistent with the presence of the expected product. To a homogeneous mixture of methyl 4'-((4,4-difluorocyclohexyl)(isobutyl) amino)-2',5-difluoro-5'-(3-(5-methylisoxazol-3-yl)ureido)-[1,1'-biphenyl]-2-carboxylate (47.1 mg, 0.082 mmol) in anhydrous tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) was added lithium hydroxide (19.56 mg, 0.817 mmol). The mixture was stirred for 21 hours. The reaction was concentrated in vacuo to remove volatiles then treated with 2 mL of water. 1 N hydrochloric acid was then added until the pH was ca.4. The resulting mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with brine then concentrated in vacuo to afford the crude product.The residue was redissolved in 1.5mL DMF and passed through a syringe filter. The crude material was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 150 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.6 mg, MS(ES): m/z = 563 [M+H]+ HPLC Tr: 1.88k. 1H NMR (500MHz, DMSO-d6) δ 10.44 (br. s., 1H), 8.84 (br. s., 1H), 8.24 - 8.07 (m, 1H), 7.94 - 7.73 (m, 1H), 7.33 (t, J=8.2 Hz, 1H), 7.24 (d, J=9.4 Hz, 1H), 7.20 (d, J=11.4 Hz, 1H), 6.38 (br. s., 1H), 2.88 - 2.76 (m, 2H), 2.35 (d, J=3.0 Hz, 3H), 2.09 - 1.91 (m, 4H), 1.87 - 1.69 (m, 2H), 1.58 (q, J=12.2 Hz, 2H), 1.44 - 1.31 (m, 1H), 0.89 - 0.82 (m, 6H).
    • Example 519 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1471
    • 519A. Methyl 5'-amino-4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1472
  • To a stirred solution of 4-bromo-N1-(4,4-difluorocyclohexyl)-5-fluoro-N1-isobutylbenzene-1,2-diamine (150 mg, 0.396 mmol) in dry dioxane (3 mL) was added methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (133 mg, 0.475 mmol), followed by potassium phosphate (252 mg, 1.187 mmol). The reaction mixture was purged with argon for 15 minutes before adding PdCl2(dppf) (57.9 mg, 0.079 mmol). The reaction mixture was again purged with argon for another 5 minutes before the reaction was equipped with a Vigreaux column and heated to 80°C under an argon atmosphere. After heating for 5 hour, LCMS suggests partial conversion to product. Reaction was again purged with argon for 15min before 62.5 mg of the boronate reagent and 49 mg of the Pd catalyst were added. Argon was bubbled through the reaction mixture for 5 minutes before heating again at 80°C. The reaction was stirred overnight. Reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed sequentially with water then brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark brown oil (528.3 mg). The crude product was purified on an Isco CombiFlash System using a 24 g silica gel column. The product was eluted with a gradient of 0-50% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product (53 mg). MS(ES): m/z = 453 [M+H]+.
    • 519B. Methyl 4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1473
  • To a solution of methyl 5'-amino-4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylate (52.8 mg, 0.117 mmol) in anhydrous tetrahydrofuran (2 mL) was added 1-isocyanato-4-methylbenzene (21.75 mg, 0.163 mmol). The mixture was warmed to 50 °C under nitrogen atmosphere. After 2 hours, heating was stopped and the reaction allowed to stir at room temperature overnight.The reaction was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic extracts were washed once each with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to afford a dark brown residue (106.6 mg). The crude product was purified on Isco CombiFlash System using a 12 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a colorless glass (56 mg). MS(ES): m/z = 586 [M+H]+.
    • 519. 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1474
  • To a homogeneous mixture of methyl 4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylate (56.0 mg, 0.096 mmol) in anhydrous tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL), at room temperature under nitrogen, was added lithium hydroxide (22.90 mg, 0.956 mmol). The reaction was stirred overnight. The reaction was concentrated in vacuo to remove volatiles then treated with 2 mL of water. Hydrochloric acid (1N) was then added until ca. pH 4. The resulting mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with brine. Evaporation then afforded a glassy residue. The crude product was purified on an Isco CombiFlash System using a 12 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Appropriate fractions containing expected product peak were combined and concentrated to remove volatiles then lyophilized to afford a white solid (21.1mg). MS(ES): m/z = 572 [M+H]+, HPLC Tr: 12.97g. 1H NMR (400MHz, DMSO-d6) δ 12.79 (br. s., 1H), 9.45 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.00 - 7.87 (m, 2H), 7.46 - 7.32 (m, 3H), 7.25 (dd, J=9.6, 2.5 Hz, 1H), 7.16 (d, J=11.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 2.96 - 2.78 (m, 3H), 2.26 (s, 3H), 2.14 - 1.93 (m, 4H), 1.93 - 1.68 (m, 2H), 1.65 - 1.50 (m, 2H), 1.42 (dquin, J=13.2, 6.7 Hz, 1H), 0.88 (d, J=6.6 Hz, 6H).
    • Example 520 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1475
  • Example 520 was prepared using the chemistry described for Example 518. MS(ES): m/z = 630 [M+H]+, HPLC Tr: 2.13k. 1H NMR (500MHz, DMSO-d6) δ 9.54 (br. s., 1H), 8.17 (s, 1H), 8.01 - 7.88 (m, 4H), 7.53 (s, 1H), 7.35 (td, J=8.5, 2.7 Hz, 1H), 7.26 (dd, J=9.4, 2.5 Hz, 1H), 7.18 (d, J=11.4 Hz, 1H), 5.06 (q, J=9.2 Hz, 2H), 2.88 - 2.78 (m, 3H), 2.14 - 1.92 (m, 4H), 1.91 - 1.71 (m, 2H), 1.62 - 1.47 (m, 2H), 1.38 (dquin, J=13.3, 6.6 Hz, 1H), 0.86 (d, J=6.9 Hz, 6H).
    • Example 521 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(3-methylisoxazol-5-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1476
  • Example 521 was prepared using the chemistry described for Example 518. MS(ES): m/z = 675 [M+H]+, HPLC Tr: 2.12k. 1H NMR (500MHz, DMSO-d6) δ 11.29 (br. s., 1H), 8.28 (br. s., 1H), 8.09 (dd, J=8.2, 3.2 Hz, 1H), 7.99 - 7.90 (m, 2H), 7.40 - 7.32 (m, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.22 (d, J=11.4 Hz, 1H), 2.82 (br. s., 3H), 2.16 (d, J=3.5 Hz, 3H), 2.09 - 1.94 (m, 4H), 1.90 - 1.71 (m, 2H), 1.61 - 1.47 (m, 2H), 1.43 - 1.30 (m, 1H), 0.91-0.80 (m, 6H)
    • Example 522 4'-(Cyclohexyl(isobutyl)amino)-2',5-difluoro-5'-(3-(6-methylpyridazin-3-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1477
    • 522A. N-Cyclohexylisobutyramide
  • Figure imgb1478
  • A solution of cyclohexanamine (3.65 g, 36.8 mmol) in anhydrous tetrahydrofuran (30 mL) was cooled to 0 °C under nitrogen. Triethylamine (5.60 mL, 40.1 mmol) was added. The mixture was stirred at 0 °C for 10 minutes before isobutyryl chloride (3.51 mL, 33.5 mmol) was added dropwise via syringe. The mixture was allowed to warm slowly to room temperature. After three days, the reaction was quenched with saturated sodium bicarbonate solution then extracted with four portions of methylene chloride. The combined organic extracts were washed with 1N hydrochloric acid and brine. The aqueous layer was further extracted with three portions of 5% MeOH/CHCl3. No product is apparent in aqueous layer, which was then discarded. The organic extracts were combined with the original organic layer and concentrated in vacuo to afford an off-white solid (5.43g). The crude product was purified on an Isco CombiFlash System using a 120 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a colorless solid (5.05 g). 1H NMR (400MHz, CHLOROFORM-d) δ 5.28 (br. s., 1H), 3.92 - 3.60 (m, 1H), 2.32 (spt, J=6.9 Hz, 1H), 2.01 - 1.86 (m, 2H), 1.81 - 1.69 (m, 2H), 1.51 - 1.33 (m, 2H), 1.17 (d, J=6.8 Hz, 6H) (some resonances are obscured by the methyls of the isobutyl group).
    • 522B. N-Isobutylcyclohexanamine
  • Figure imgb1479
  • Lithium aluminum hydride (48 mL, 48.0 mmol, 1M in tetrahydrofuran) was slowly added to a solution of N-cyclohexylisobutyramide (4 g, 23.63 mmol) in anhydrous tetrahydroduran (100 mL) under nitrogen. The resulting solution was heated at 70 °C for 20 hours. The reaction mixture was cooled to room temperature then diluted with ether and cooled in an ice bath to 0°C. Water (2 mL) was slowly added to the reaction mixture followed by 15% aqueous sodium hydroxide (2 mL). Water (6mL) was then added and the reaction mixture was removed from the ice bath and allowed to warm to room temperature. The mixture was stirred for 15 minutes at room temperature before magnesium sulfate was added and the mixture stirred for another 15 minutes. The mixture was filtered through a fritted glass funnel to remove salts. The filtrate was transferred to a separatory funnel where the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic extracts were washed with water then brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford an oil (2.9573g). This material was used without purification. 1H NMR (400MHz, DMSO-d6) δ 2.52 (dt, J=3.6, 1.9 Hz, 1H), 2.33 (d, J=6.8 Hz, 2H), 1.88 - 1.75 (m, 2H), 1.73 - 1.63 (m, 2H), 1.62 - 1.48 (m, 2H), 1.27 - 1.09 (m, 4H), 1.06 - 0.93 (m, 2H), 0.87 (d, J=6.6 Hz, 6H).
    • 522C. 4-Bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline
  • Figure imgb1480
  • To a solution of 5-bromo-2,4-difluoronitrobenzene (1.806 g, 7.59 mmol) in anhydrous NMP (3 mL) was added diisopropylethylamine (3.98 mL, 22.77 mmol) followed by N-isobutylcyclohexanamine (1.2964 g, 8.35 mmol) in NMP (6 mL). The mixture was heated at 110 °C under nitrogen. After stirring for 19 hours, the reaction was allowed to cool to room temperature before being diluted with ether. The ether solution was washed twice with 1N hydrochloric acid. The organic layer was then washed twice with each saturated sodium bicarbonate solution then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark residue (3.06g). The crude product was purified on an Isco CombiFlash System using a 80 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a red-orange solid (2.30 g). 1H NMR (400MHz, CHLOROFORM-d) δ 7.99 (d, J=7.3 Hz, 1H), 6.89 (d, J=11.0 Hz, 1H), 2.97 - 2.90 (m, 1H), 2.89 (d, J=7.3 Hz, 2H), 1.91 - 1.77 (m, 4H), 1.71 (dt, J=13.5, 6.8 Hz, 1H), 1.67 - 1.58 (m, 1H), 1.50 - 1.38 (m, 2H), 1.34 - 1.18 (m, 2H), 1.16 - 1.02 (m, 1H), 0.92 (d, J=6.6 Hz, 6H). MS(ES): m/z = 373 [M+H]+.
    • 522D. 4-Bromo-N1-cyclohexyl-5-fluoro-N1-isobutylbenzene-1,2-diamine
  • Figure imgb1481
  • A solution of 4-bromo-N-cyclohexyl-5-fluoro-N-isobutyl-2-nitroaniline (1.116 g, 2.99 mmol) in ethanol (20 mL) and water (4.00 mL) was cooled to 0°C under nitrogen. Zinc (3.91 g, 59.8 mmol) and ammonium chloride (3.20 g, 59.8 mmol) were then added. The mixture was stirred at room temperature for an hour. The reaction mixture was filtered through a pad of Celite which was then thoroughly rinsed with chloroform. The combined organic filtrates were concentrated in vacuo to afford a waxy, gold residue (1.1283g). The sample was suspended in chloroform. The sample was filtered and the filtrate applied to a 40 g Isco silica gel column. The product was eluted with 0-100% ethyl acetate in hexanes. Only partial purification was achieved. Concentrate product containing fractions. The partially purified product was purified on Isco CombiFlash System using a 40 g silica gel column. The product was eluted with a gradient of 0-50% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a gold oil (246 mg). 1H NMR (400MHz, DMSO-d6) δ 7.00 (d, J=10.8 Hz, 1H), 7.11 - 6.96 (m, 1H), 6.91 (d, J=7.3 Hz, 1H), 4.80 (s, 2H), 2.89 - 2.67 (m, 2H), 2.60 (tt, J=11.7, 3.2 Hz, 1H), 1.73 (br. s., 4H), 1.55 (d, J=9.9 Hz, 1H), 1.44 - 1.28 (m, 3H), 1.16 - 0.95 (m, 3H), 0.80 (d, J=6.6 Hz, 6H). MS(ES): m/z = 343 [M+H]+.
    • 522E. Methyl5'-amino-4'-(cyclohexyl(isobutyl)amino)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1482
  • To a stirred solution of 4-bromo-N1-cyclohexyl-5-fluoro-N1-isobutylbenzene-1,2-diamine (246 mg, 0.717 mmol) in dry dioxane (5 mL) was added methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (241 mg, 0.860 mmol), followed by potassium phosphate (456 mg, 2.150 mmol). The reaction was purged with argon for 15 minutes. PdCl2(dppf) (105 mg, 0.143 mmol) was added and purging with argon continued for 5 minutes. The reaction was then heated to 80°C. The reaction was heated for ca. 24 hours. The cooled reaction was evaporated then resuspended in ethyl acetate. The mixture was washed sequentially with water and then brine, The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark brown residue (953.5mg). Purification was attenpted on a CombiFlash System using a 40 g Isco silica gel column. The column was eluted with a gradient of 0-100% ethyl acetate in hexanes. As only partial purification was achieved the material was purified a second time on the Isco CombiFlash System using a 24 g silica gel column. The product was eluted with a 0-50% ethyl acetate in hexanes gradient. Evaporation of the appropriate fractions gave the desired product as an oil (144.7 mg). 1H NMR (400MHz, DMSO-d6) δ 7.88 (dd, J=8.7, 6.1 Hz, 1H), 7.34 (td, J=8.5, 2.6 Hz, 1H), 7.28 (dd, J=9.9, 2.6 Hz, 1H), 6.87 (d, J=12.1 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 4.65 (s, 2H), 3.60 (s, 3H), 2.78 (br. s., 2H), 2.75 - 2.64 (m, 1H), 1.77 (t, J=11.1 Hz, 4H), 1.58 (d, J=10.6 Hz, 1H), 1.49 - 1.35 (m, 3H), 1.19 - 1.00 (m, 3H), 0.84 (d, J=6.6 Hz, 6H)
    • 522. 4'-(Cyclohexyl(isobutyl)amino)-2',5-difluoro-5'-(3-(6-methylpyridazin-3-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • The rest of the preparation was accomplished as in Example 518. MS(ES): m/z = 538 [M+H]+, HPLC Tr: 1.82j. 1H NMR (500MHz, DMSO-d6) δ 10.32 (br. s., 1H), 8.09 (d, J=8.4 Hz, 1H), 7.91 (dd, J=8.7, 6.2 Hz, 1H), 7.63 (br. s., 1H), 7.51 (d, J=9.4 Hz, 1H), 7.33 (td, J=8.4, 2.5 Hz, 1H), 7.26 (dd, J=9.7, 2.2 Hz, 1H), 7.11 (d, J=11.9 Hz, 1H), 2.84 (d, J=6.4 Hz, 2H), 2.69 (t, J=11.6 Hz, 1H), 2.53 (s, 3H), 2.00 - 1.87 (m, 2H), 1.67 (d, J=9.4 Hz, 2H), 1.52 (br. s., 1H), 1.44 (dt, J=13.4, 6.7 Hz, 1H), 1.40 - 1.27 (m, 2H), 1.14 - 0.97 (m, 3H), 0.86 (d, J=6.4 Hz, 6H).
    • Example 523 4'-(Cyclohexyl(isobutyl)amino)-5'-(3-(4-cyclohexylphenyl)ureido)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1483
  • Example 523 was prepared using the chemistry described for Example 522. MS(ES): m/z = 604 [M+H]+, HPLC Tr: 2.78k. 1H NMR (500MHz, DMSO-d6) δ 9.41 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.91 (dd, J=8.7, 6.2 Hz, 1H), 7.80 (s, 1H), 7.36 (d, J=8.9 Hz, 2H), 7.34 - 7.29 (m, 1H)(partially obscured), 7.25 (dd, J=9.4, 2.5 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.07 (d, J=11.4 Hz, 1H), 2.81 (d, J=5.9 Hz, 2H), 2.66 - 2.57 (m, 1H), 2.47 - 2.39 (m, 1H), 1.87 (d, J=10.9 Hz, 2H), 1.81 - 1.66 (m, 7H), 1.53 (d, J=11.4 Hz, 1H), 1.46 - 1.17 (m, 8H), 1.16 - 0.95 (m, 3H).
    • Example 524 4'-(Cyclohexyl(isobutyl)amino)-2',5-difluoro-5'-(3-(4-morpholinophenyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1484
  • Example 524 was prepared using the chemistry described for Example 522. MS(ES): m/z = 607 [M+H]+, HPLC Tr: 2.04k. 1H NMR (500MHz, DMSO-d6) δ 9.23 (br. s., 1H), 8.00 (d, J=8.4 Hz, 1H), 7.91 (dd, J=8.9, 5.9 Hz, 1H), 7.74 (s, 1H), 7.39 - 7.33 (m, 1H), 7.31 (d, J=8.9 Hz, 2H), 7.25 (dd, J=9.7, 2.7 Hz, 1H), 7.07 (d, J=11.4 Hz, 1H), 6.90 (d, J=8.9 Hz, 2H), 3.79 - 3.69 (m, 4H), 3.08 - 3.00 (m, 4H), 2.79 (d, J=5.0 Hz, 2H), 2.59 (t, J=11.4 Hz, 1H), 1.84 (d, J=9.9 Hz, 2H), 1.71 (d, J=12.4 Hz, 2H), 1.53 (d, J=11.4 Hz, 1H), 1.39 (dquin, J=13.3, 6.6 Hz, 1H), 1.32 - 1.19 (m, 2H), 1.16 - 0.95 (m, 3H), 0.85 (d, J=6.4 Hz, 6H).
    • Example 525 4'-(Cyclohexyl(isobutyl)amino)-2',5-difluoro-5'-(3-(5-methylpyrazin-2-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1485
  • Example 525 was prepared using the chemistry described for Example 522. MS(ES): m/z = 538 [M+H]+, HPLC Tr: 2.28k. 1H NMR (500MHz, DMSO-d6) δ 10.24 (s, 1H), 8.59 (br. s., 1H), 8.16 - 8.08 (m, 2H), 7.98 - 7.88 (m, 2H), 7.35 (td, J=8.4, 2.5 Hz, 1H), 7.29 (dd, J=9.7, 2.7 Hz, 1H), 7.13 (d, J=11.4 Hz, 1H), 2.86 (d, J=5.4 Hz, 2H), 2.71 - 2.61 (m, 1H), 2.43 (s, 3H), 1.87 (d, J=10.9 Hz, 2H), 1.67 (d, J=12.4 Hz, 2H), 1.52 (d, J=10.9 Hz, 1H), 1.43 (dquin, J=13.4, 6.7 Hz, 1H), 1.37 - 1.25 (m, 2H), 1.13 - 0.96 (m, 3H), 0.87 (d, J=6.4 Hz, 6H).
    • Example 526 4'-(Diisobutylamino)-3'-(3-(2-fluorophenyl)ureido)-5-methyl-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1486
    • 526A. 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline
  • Figure imgb1487
  • 4-bromo-N,N-diisobutyl-2-nitroaniline (20 g, 60.7 mmol)(lA), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (15.09 g, 66.8 mmol), PdCl2(dppf)-CH2Cl2 adduct (1.111 g, 1.519 mmol) and potassium acetate (17.89 g, 182 mmol) were combined in a round bottom flask. Dimethylsulfoxide (200 mL) was added and the flask evacuated and back-filled with nitrogen 3 times. The reaction was then heated at 80 °C for 8 h. The reaction was cooled to room temperature, divided in half, and passed through a two short silica gel plugs. The silica gel was rinsed with hexane/ethyl acetate (4:1) (3x100mL). After removal of the solvent, the crude product was purified on a 750 g RediSep silica gel column using a 0-10% ethyl acetate in hexanes gradient. 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline (22.17 g) was obtained as a yellow/orange oil. 1H NMR (400MHz, CHLOROFORM-d) δ 8.15 (d, J=1.5 Hz, 1H), 7.75 (dd, J=8.4, 1.5 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 3.76 (s, 4H), 3.09 - 2.89 (m, 4H), 1.95 (dquin, J=13.5, 6.8 Hz, 2H), 1.03 (s, 6H), 0.85 (d, J=6.6 Hz, 12H).
    • 526B. Methyl 4'-(diisobutylamino)-5-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1488
  • A 20 mL vial was charged with 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline (300 mg, 0.828 mmol), methyl 2-bromo-4-methylbenzoate (158 mg, 0.690 mmol) and cesium carbonate (675 mg, 2.070 mmol). The vial was sealed, evacuated, and back-filled with argon (x3). Dioxane-water (3:1, 3.0 mL) was then added and the mixture purged again with argon. PdCl2(dppf)-CH2Cl2 adduct (56.4 mg, 0.069 mmol) was added and the reaction vial then sealed and heated at 100 °C. The reaction was heated for ca. 5 hours. The cooled reaction was transferred to a separatory funnel and diluted with ethyl acetate. The organic layer was washed with water. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic extracts were washed with water then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a dark brown residue (637mg). The crude product was purified on Isco CombiFlash System using a 12 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a viscous orange red oil (292.5 mg).
    1H NMR (400MHz, CHLOROFORM-d) δ 7.82 (d, J=7.9 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.33 (dd, J=8.6, 2.2 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.22 - 7.19 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 3.69 (s, 3H), 3.00 (d, J=7.0 Hz, 4H), 2.45 (s, 3H), 2.05 - 1.92 (m, 2H), 0.90 (d, J=6.6 Hz, 12H).
    • 526C. Methyl 3'-amino-4'-(diisobutylamino)-5-methyl-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1489
  • To a solution of methyl 4'-(diisobutylamino)-5-methyl-3'-nitro-[1,r-biphenyl]-2-carboxylate (275 mg, 0.690 mmol) in ethanol (3.5 mL) and water (0.5 mL), at 0°C under nitrogen, was added zinc (271 mg, 4.14 mmol) and ammonium chloride (221 mg, 4.14 mmol). The mixture was stirred at room temperature for 4 hours then placed in refrigerator overnight. The reaction was filtered through a pad of Celite which was then thoroughly rinsed with chloroform. The filtrate was concentrated in vacuo to afford an oily residue (313.3 mg). The crude product was purified on Isco CombiFlash System using a 12 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as an amber oil (150.1 mg). 1H NMR (400MHz, CHLOROFORM-d) δ 7.69 (d, J=7.7 Hz, 1H), 7.23 (d, J=1.1 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.08 (d, J=7.9 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 6.65 (dd, J=8.0, 2.1 Hz, 1H), 4.24 - 4.16 (m, 2H), 3.62 (s, 3H), 2.68 (d, J=7.3 Hz, 4H), 2.43 (s, 3H), 1.82 (dquin, J=13.5, 6.8 Hz, 2H), 0.96 (d, J=6.6 Hz, 12H).
    • 526. 4'-(Diisobutylamino)-3'-(3-(2-fluorophenyl)ureido)-5-methyl-[1,r-biphenyl]-2-carboxylic acid
  • The rest of the preparation was accomplished as in Example 519. MS(ES): m/z = 492 [M+H]+, HPLC Tr: 2.11k. 1H NMR (500MHz, DMSO-d6) δ 9.38 (br. s., 1H), 8.16 (d, J=4.0 Hz, 1H), 8.05 - 7.94 (m, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.58 (dd, J=7.4, 4.5 Hz, 1H), 7.30 - 7.09 (m, 5H), 7.08 - 6.99 (m, 1H), 6.97 - 6.87 (m, 1H), 2.73 (d, J=2.0 Hz, 4H), 2.38 (d, J=3.5 Hz, 3H), 1.79 - 1.64 (m, 2H), 0.96 - 0.81 (m, 12H).
    • Example 527 3'-(3-(4-Chloro-2-fluorophenyl)ureido)-4'-(diisobutylamino)-5-methyl-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1490
  • Example 527 was prepared using the procedures described for Example 526. MS(ES): m/z = 526 [M+H]+, HPLC Tr: 2.20k
    • Example 528 3'-(3-(2,4-Difluorophenyl)ureido)-4'-(diisobutylamino)-5-methyl-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1491
  • Example 528 was prepared using the procedures described for Example 526. MS(ES): m/z = 510 [M+H]+ HPLC Tr: 2.16k. 1H NMR (500MHz, METHANOL-d4) δ 7.94 (d, J=2.0 Hz, 1H), 7.78 (td, J=8.9, 5.9 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.20 - 7.13 (m, 2H), 7.02 (dd, J=8.4, 2.0 Hz, 1H), 6.95 - 6.79 (m, 2H), 2.70 (d, J=7.4 Hz, 4H), 2.40 (s, 3H), 1.78 (dquin, J=13.4, 6.7 Hz, 2H), 0.91 (d, J=6.4 Hz, 12H).
    • Example 529 4'-(Diisobutylamino)-3'-(3-(4-ethoxyphenyl)ureido)-5-methyl-[1,r-biphenyl]-2-carboxylic acid
  • Figure imgb1492
  • Example 529 was prepared using the procedures described for Example 526. MS(ES): m/z = 518 [M+H]+, HPLC Tr: 2.14k. 1H NMR (500MHz, METHANOL-d4) δ 8.02 (d, J=2.0 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.60 (s, 1H), 7.29 (d, J=8.9 Hz, 2H), 7.25 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.98 (dd, J=8.4, 2.0 Hz, 1H), 6.89 - 6.80 (m, 2H), 4.02 (q, J=6.9 Hz, 2H), 2.64 (d, J=6.9 Hz, 4H), 2.40 (s, 3H), 1.72 (dquin, J=13.5, 6.7 Hz, 2H), 1.40 (t, J=6.9 Hz, 3H), 0.86 (d, J=6.4 Hz, 12H).
    • Example 530 4'-(Diisobutylamino)-5-methyl-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1493
  • Example 530 was prepared using the procedures described for Example 526. MS(ES): m/z = 488 [M+H]+, HPLC Tr: 2.16k, 1H NMR (500MHz, DMSO-d6) δ 9.39 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.90 (s, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.22 (dd, J=7.7, 3.7 Hz, 2H), 7.18 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.90 (dd, J=7.9, 2.0 Hz, 1H), 2.71 (d, J=6.9 Hz, 4H), 2.38 (s, 3H), 2.25 (s, 3H), 1.70 (dquin, J=13.3, 6.6 Hz, 2H), 0.88 (d, J=6.4 Hz, 12H).
    • Example 531 5'-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1494
    • 531A. 1-(Benzo[d][1,3]dioxol-5-yl)-3-(5-bromo-2-((4,4-difluorocyclohexyl) (isobutyl)amino)-4-fluorophenyl)urea
  • Figure imgb1495
  • To a solution of 4-bromo-N1-(4,4-difluorocyclohexyl)-5-fluoro-N1-isobutylbenzene-1,2-diamine (60 mg, 0.158 mmol)(Intermediate 518D) in anhydrous tetrahydrofuran (1mL) was added 3,4-(methylenedioxy)phenyl isocyanate (43.9 mg, 0.269 mmol). The tube was sealed and the resulting mixture was heated at 50 °C for 0.5 hour and then allowed to stir at room temperature overnight. The crude product was purified on an Isco CombiFlash System using a 24 g silica gel column. The product was eluted with a gradient of 0-50% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a glass (71.2 mg). MS(ES): m/z = 542 [M+H]+.
    • 531. 5'-(3-(Benzo[d][1,3]dioxol-5-yl)ureido)-4'-((4,4-difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1496
  • To a stirred solution of 1-(benzo[d][1,3]dioxol-5-yl)-3-(5-bromo-2-((4,4-difluorocyclohexyl)(isobutyl)amino)-4-fluorophenyl)urea (35.6 mg, 0.066 mmol) in argon-purged dimethylformamide (1 mL) was added 2-borono-4-fluorobenzoic acid (24.14 mg, 0.131 mmol), followed by potassium carbonate (0.219 mL, 0.328 mmol, 1.5 M aqueous). The reaction was purged with argon for 15 minutes and then Pd(Ph3P)4 (7.58 mg, 6.56 µmol) was added. Purging with argon was continued for another 5 minutes. The vial was then capped vial and heated to 100°C. The reaction was heated for 2.25 hours then allowed to cool to room temperature. The reaction was treated with dropwise addition of glacial acetic acid until ca. pH 4, then diluted with 1.5 mL dimethylformamide. The reaction was filtered through an Acrodisc (13mm syringe filter with 0.45µm Nylon membrane) syringe filter. The crude material was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 150 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the final product (7.2 mg). MS(ES): m/z = 602 [M+H]+, HPLC Tr: 2.18k, 1H NMR (500MHz, METHANOL-d4) δ 8.05 (d, J=7.9 Hz, 1H), 8.00 - 7.94 (m, 1H), 7.19 - 7.06 (m, 2H), 7.00 (s, 1H), 6.89 (d, J=11.4 Hz, 1H), 6.79 - 6.74 (m, 2H), 5.95 (s, 2H), 2.75 (d, J=6.4 Hz, 3H), 2.04 (br. s., 2H), 1.82 - 1.58 (m, 6H), 1.55 - 1.43 (m, 1H), 0.84 (d, J=6.4 Hz, 6H).
    • Example 532 1-(Benzo [d][1,3]dioxol-5-yl)-3-(4-((4,4-difluorocyclohexyl)(isobutyl)amino)-6-fluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)urea
  • Figure imgb1497
  • Example 532 was prepared using the methodology shown for Example 531. MS(ES): m/z = 608 [M+H]+, HPLC Tr: 2.07k.
    • Example 533 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2'-fluoro-5'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1498
  • Example 533 was prepared using the methodology shown for Example 531. MS(ES): m/z = 554 [M+H]+, HPLC Tr: 2.26k, 1H NMR (500MHz, METHANOL-d4) δ 8.08 - 8.02 (m, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.48 - 7.40 (m, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 6.88 (d, J=10.9 Hz, 1H), 2.75 (d, J=5.9 Hz, 3H), 2.32 (s, 3H), 2.09 - 1.99 (m, 2H), 1.81 - 1.56 (m, 6H), 1.50 (dquin, J=13.4, 6.7 Hz, 1H), 0.85 (d, J=6.4 Hz, 6H).
    • Example 534 1-(4-((4,4-Difluorocyclohexyl)(isobutyl)amino)-6-fluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(p-tolyl)urea
  • Figure imgb1499
  • Example 534 was prepared using the methodology shown for Example 531. MS(ES): m/z = 578 [M+H]+, HPLC Tr: 2.23k, 1H NMR (500MHz, METHANOL-d4) δ 7.86 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.60 - 7.56 (m, 1H), 7.55 - 7.49 (m, 1H), 7.30 (d, J=7.9 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 6.74 (d, J=11.4 Hz, 1H), 2.83 - 2.68 (m, 3H), 2.32 (s, 3H), 2.11 - 2.01 (m, 2H), 1.81 - 1.57 (m, 6H), 1.46 (dquin, J= 13.4, 6.7 Hz, 1H), 0.84 (d, J=6.4 Hz, 6H).
    • Example 535 4'-(Diisobutylamino)-3-methyl-3'-(3-(3-methylisoxazol-5-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1500
    • 535A. Methyl 4'-(diisobutylamino)-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1501
  • A scintillation vial was charged with 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline (300 mg, 0.828 mmol) (intermediate 526A) and methyl 2-bromo-6-methylbenzoate (158 mg, 0.690 mmol). Dioxane (3.00 mL) and water (1 mL) were then added. To this mixture was added cesium carbonate (675 mg, 2.070 mmol) and the resulting mixture was purged with argon for 15-20 min. To the reaction mixture was then added PdCl2(dppf)-CH2Cl2 adduct (56.4 mg, 0.069 mmol). The reaction mixture was purged with argon for 5 minutes more when the vial was sealed and warmed to 100 °C. After stirring overnight, the cooled reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic extracts were washed with water and then brine. The organic layer was dried over sodium sulfate filtered and concentrated in vacuo to afford a dark brown oil (428.0 mg). The crude product was purified on Isco CombiFlash System using a 24 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as an orange oil (244.2 mg). 1H NMR (400MHz, CHLOROFORM-d) δ 7.78 (d, J=2.4 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.24 (dd, J=7.4, 5.0 Hz, 2H), 7.15 (d, J=8.6 Hz, 1H), 3.69 (s, 3H), 2.99 (d, J=7.3 Hz, 4H), 2.42 (s, 3H), 1.97 (dquin, J=13.5, 6.8 Hz, 2H), 0.89 (d, J=6.6 Hz, 12H).
    • 535B. Methyl 3'-amino-4'-(diisobutylamino)-3-methyl-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1502
  • To a solution of methyl 4'-(diisobutylamino)-3-methyl-3'-nitro-[1,1'-biphenyl]-2-carboxylate (230.9 mg, 0.579 mmol) in ethanol (4.90 mL) and water (0.7 mL) under nitrogen, was added ammonium chloride (310 mg, 5.79 mmol). The mixture was stirred at room temperature for 10 min before zinc (379 mg, 5.79 mmol) was added. The reaction was stirred for 2 hours. The reaction was diluted with methylene chloride and filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford an oily residue (206.7 mg). MS(ES): m/z = 369 [M+H]+.
    • 535C. Methyl4'-(diisobutylamino)-3-methyl-3'-(3-(3-methylisoxazol-5-yl)ureido)-[1,1'-biphenyl]-2-carboxylate
  • Figure imgb1503
  • To a solution of methyl 3'-amino-4'-(diisobutylamino)-3-methyl-[1,1'-biphenyl]-2-carboxylate (34.4 mg, 0.093 mmol) in anhydrous tetrahydrofuran (2 mL) was treated with 4-nitrophenyl chloroformate (20.70 mg, 0.103 mmol). The mixture was stirred for ca. 2 hours. 5-Amino-3-methylisoxazole (73.3 mg, 0.747 mmol) and triethylamine (0.23 mL, 1.650 mmol) were added and the reaction warmed to 50 °C. After stirring overnight, the reaction was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was then extracted twice with ethyl acetate. These combined organic extracts were washed with brine. The organic layer was then concentrated in vacuo. The crude product was purified on an Isco CombiFlash System using a 12 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product as a yellow solid (14.8 mg). MS(ES): m/z = 493 [M+H]+.
    • 535. 4'-(Diisobutylamino)-3-methyl-3'-(3-(3-methylisoxazol-5-yl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1504
  • To a homogeneous mixture of methyl 4'-(diisobutylamino)-3-methyl-3'-(3-(3-methylisoxazol-5-yl)ureido)-[1,1'-biphenyl]-2-carboxylate (14.8 mg, 0.030 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL) was added lithium hydroxide (7.20 mg, 0.300 mmol). The mixture was stirred at room temperature for a day. More lithium hydroxide (7.20 mg, 0.300 mmol) and water (0.5 mL) were added. The reaction was stirred for 3 days when the temperature was raised to 40°C. After ca. 5 hours, sodium hydroxide solution (0.060 mL, 0.300 mmol, 5 M) was added and the reaction heated at 50°C. After 4 hours, the reaction was allowed to cool to room temperature. The next morning the reaction was warmed to 70°C and stirred for 5 days. The reaction was allowed to stand for 16 days when LCMS analysis suggested the presence of some of the desired product. The reaction mixture was treated with glacial acetic acid until ca. pH 4. The acidified reaction mixture was diluted with 1.5 mL dimethylformamide before being filtered through an Acrodisc (13mm syringe filter with 0.45µm Nylon membrane) syringe filter. The crude material was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 150 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM
    ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 0.8 mg of the desired product. MS(ES): m/z = 479 [M+H]+, HPLC Tr: 1.74k.
    • Example 536 4'-(Diisobutylamino)-3-methyl-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1505
  • To a solution of 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine (80 mg, 0.241 mmol) (Intermediate 4B) in anhydrous tetrahydrofuran (2.5 mL) was added 1-isocyanato-4-methylbenzene (54.5 mg, 0.409 mmol). The tube was sealed and the resulting mixture was stirred at 50 °C. The reaction was heated overnight. The reaction was then cooled and the crude product was purified on an Isco CombiFlash System using a 12 g silica gel column. The product was eluted with a gradient of 0-100% ethyl acetate in hexanes. Evaporation of the appropriate fractions gave the desired product which was dried under vacuum overnight (107.4 mg). LCMS suggests presence of boronic acid (MS(ES): m/z = 479 [M+H]+). A portion of this material 1-(2-(diisobutylamino)-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-3-(p-tolyl)urea (26.8 mg, 0.058 mmol) was dissolved in argon-purged dimethylformamide (1 mL). 2-Bromo-6-methylbenzoic acid (24.76 mg, 0.115 mmol) was added followed by potassium carbonate (0.192 mL, 0.288 mmol, 1.5 M aqueous). Purging with argon was continued for 15 minutes when Pd(Ph3P)4 (6.65 mg, 5.76 µmol) was added. The reaction was purged with argon for 5 minutes, capped, and heated to 100°C. The reaction was heated for 4 hours and then allowed to cool to room temperature. The reaction was treated with a dropwise addition of glacial acetic acid until ca. pH 4, then diluted with dimethylformamide (1.5 mL). The reaction was passed through an Acrodisc (13mm syringe filter with 0.45µm Nylon membrane) syringe filter. The crude material was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 0.8 mg of the desired product. MS(ES): m/z = 488 [M+H]+. HPLC Tr: 2.13k,1H NMR (500MHz, METHANOL-d4) δ 8.04 (s, 1H), 7.33 - 7.25 (m, 4H), 7.22 - 7.15 (m, 2H), 7.14 - 7.05 (m, 3H), 2.65 (d, J=7.4 Hz, 4H), 2.42 (s, 3H), 2.30 (s, 3H), 1.73 (dquin, J=13.4, 6.7 Hz, 2H), 0.87 (d, J=6.4 Hz, 12H).
    • Example 537 1-(4-((4,4-Difluorocyclohexyl)(isobutyl)amino)-6-fluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(2-fluorophenyl)urea
  • Figure imgb1506
  • Example 537was prepared using the procedures described for Example 531. MS(ES): m/z = 582 [M+H]+, HPLC Tr: 2.18k.
    • Example 538 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-2',5-difluoro-5'-(3-(2-fluorophenyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1507
  • Example 538 was prepared using the procedures described for Example 531. MS(ES): m/z = 576 [M+H]+. HPLC Tr: 1.93k.
    • Example 539 1-(4-((4,4-Difluorocyclohexyl)(isobutyl)amino)-6-fluoro-2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)-3-(4-ethoxyphenyl)urea
  • Figure imgb1508
  • Example 539 was prepared using the procedures described for Example 531. MS(ES): m/z = 608 [M+H]+. HPLC Tr: 1.88k.
    • Example 540 4'-((4,4-Difluorocyclohexyl)(isobutyl)amino)-5'-(3-(4-ethoxyphenyl)ureido)-2',5-difluoro-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1509
  • Example 540 was prepared using the procedures described for Example 531. MS(ES): m/z = 602 [M+H]+. HPLC Tr: 1.96k.
    • Example 541 4'-(Dicyclopropylamino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1510
    • 541A. 1-(5-Bromo-2-(dicyclopropylamino)phenyl)-3-(p-tolyl)urea
  • Figure imgb1511
  • To a solution of 4-bromo-N1,N1-dicyclopropylbenzene-1,2-diamine (30 mg, 0.112 mmol) (Intermediate 509B) in anhydrous tetrahydrofuran (1mL), in a sealable tube, was added 1-isocyanato-4-methylbenzene (0.024 mL, 0.191 mmol). The tube was sealed and the resulting mixture was heated at 50 °C The reaction was heated for ca. 1.5 hour. The reaction was quenched with water then partitioned between ethyl acetate and brine. The layers were separated and the aqueous layer extracted twice more with ethyl acetate. The organic extracts were combined and concentrated in vacuo to afford a tan solid (60.8 mg). LCMS suggests the presence of the desired product and N,N'-ditoluylurea. Use this material directly in the next transformation.
    • 541. 4'-(Dicyclopropylamino)-5-fluoro-3'-(3-(p-tolyl)ureido)-[1,1'-biphenyl]-2-carboxylic acid
  • Figure imgb1512
  • To a stirred solution of 1-(5-bromo-2-(dicyclopropylamino)phenyl)-3-(p-tolyl)urea (22.5 mg, 0.056 mmol) in argon-purged dimethylformamide (1 mL) was added 2-borono-4-fluorobenzoic acid (20.68 mg, 0.112 mmol), followed by an aqueous solution of potassium carbonate (0.187 mL, 0.281 mmol, 1.5 M). The reaction was purged with argon for 15 minutes then Pd(Ph3P)4 (6.49 mg, 5.62 µmol) was added. Purging with argon was continued for another 5 minutes when the vial was capped and heated to 100°C. Heating was continued for 6 hours when the reaction was allowed to cool to room temperature. After 3 days, the reaction was treated with the dropwise addition of glacial acetic acid until ca. pH 4. The reaction was then diluted with 1.5mL dimethylformamide and filtered through an Acrodisc (13mm syringe filter with 0.45 µm Nylon membrane) syringe filter. The crude material was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.3 mg. MS(ES): m/z = 460 [M+H]+. HPLC Tr: 2.17k, 1H NMR (500MHz, METHANOL-d4) δ 8.11 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.4, 5.9 Hz, 1H), 7.27 (dd, J=7.9, 3.0 Hz, 3H), 7.16 (dd, J=9.9, 2.5 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.07 (td, J=8.4, 2.5 Hz, 1H), 7.01 (dd, J=8.4, 2.0 Hz, 1H), 2.62 - 2.53 (m, 2H), 2.32 (s, 3H), 0.49 (d, J=5.9 Hz, 4H), 0.39 (br. s., 4H).
  • Using the methods described herein, the following additional compounds of the invention were prepared.
    Example No. Compound HPLC Tr (M+H)+
    542
    Figure imgb1513
    543
    Figure imgb1514
         		2.14k 490
    544
    Figure imgb1515
         		2.04k 496
    545
    Figure imgb1516
         		2.15k 518
    • EVALUATION OF BIOLOGICAL ACTIVITY
  • Exemplary compounds were tested for inhibition of IDO activity. Experimental procedures and results are provided below.
    • IDO Kynurenine Assay with Human IDO1/HEK293 Cells
  • Human IDO1/HEK293 cells were seeded at 10,000 cells per 50uL per well with RPMI/phenol red free media contains 10% FBS in a 384-well black wall clear bottom tissue culture plate (Matrix Technologies LLC) 125nL of certain concentration of compound was then added to each well using ECHO liquid handling systems. The cells were incubated for 20 hours in 37 °C incubator with 5% CO2.
  • The compound treatments were stopped by adding Trichloroacetic Acid(Sigma-Aldrich) to a final concentration at 0.2%. The cell plate was further incubated at 50°C for 30 minute. The equal volume supernatant (20uL) and 0.2% (w/v) Ehrlich reagent (4-dimethylaminobenzaldehyde, Sigma-Aldrich) in glacial acetic acid were mixed in a new clear bottom 384-well plate. This plate was then incubated at room temperature for 30 minute. The absorbance at 490 nm was measured on Envision plate reader.
  • Compound IC50 values were calculated using the counts of 500 nM of a reference standard treatment as one hundred percent inhibition, and counts of no compound but DMSO treatment as zero percent inhibition.
    • Reagents:Hela cells (ATCC, CCL-2)
    • IFNg (R&D, 28-IF-100)-- resuspend at 10 ug/mL in PBS with 0.1% BSA
    • 30% TCA
    • Ehrlich reagent (2% w/v p-dimethylaminobenzaldehyde in glacial acetic acid)
    • Cell Titer 96 Aqueous Non-Radioactive Cell Proliferation Assay, MTS (Promega, Cat # G5430)
    Cell lines and culture conditions
  • Hela cancer cell lines were acquired from the American Type Culture Collection. Cells were maintained in phenol red free-RPMI1640 medium containing high glucose and L-glutamine (Invitrogen) supplemented with 10% fetal bovine serum (FBS; Invitrogen). Cell cultures were incubated at 37°C, 5% CO2, and 100% humidity.
    • Cell Treatment and Kynurenine Assay
  • Hela cells were seeded on 96-well plates (40,000 cells per well) and allowed to adhere for 5-6 hours. Cells were then treated with vehicle (DMSO) or with IDO inhibitor at a top dose of 30µM (3-fold dilution all the way down to 1.5nM). A final concentration of 100 ng/mL of human recombinant IFN-γ (R&D, 28-IF-100) was immediately added to the cells to stimulate IDO expression. Treated cells were then incubated for 20 hours at 37°C. At the end of the 20h incubation, reactions were terminated by the addition of 30% TCA to each well. Plates were incubated for 30 minutes at 50°C to hydrolyze N-formylkynurenine to kynurenine. Cells were centrifuged 10 minutes at 2400 rpm. 100 ul of supernatants were transfered to new 96 flat well plates and mixed with 100 ul Ehrlich reagent. The resulting solution was incubated 10 minutes at RT. Absorbance at 490 nM was read using Spectra Max 384 (Molecular Devices).
  • Results of the IDO assays are shown in the table below.
    Ex. No. HEK human IDO-1 (IC50, uM) Hela Kyurenine (IC50, uM) LLE_IDO_ABS_DR (IC50, uM)
    1 3.31E-03 1.37E-03 3.45E-03
    2 0.02 0.09
    3 0.01 0.06
    4 0.08
    5 4.05E-03
    6 6.47E-03
    7 0.02
    8 0.18
    9 0.35
    10 0.10
    11 0.25
    12 0.22
    13 0.06 0.03
    14 0.10 0.08
    15 0.09
    16 0.02 0.01
    17 0.27
    18 0.63
    19 0.04 0.02
    20 0.13
    21 0.15
    22 0.03
    23 0.45
    24 0.01
    25 0.03
    26 0.37
    27 2.55E-03
    28 0.01
    29 4.76E-03
    30 5.19E-03
    31 5.18E-03
    32 2.54E-03
    33 4.99E-03
    34 4.01E-03
    35 0.01
    36 5.90E-03
    37 0.01 0.04
    38 1.78E-03 1.84E-03
    39 2.37E-03 1.00E-03
    40 0.01 3.79E-03
    41 6.31E-03 1.78E-03
    42 1.17
    43 1.43
    44 1.72E-03 7.93E-03
    45 0.01 0.06
    46 0.09 0.13
    47 0.01 0.04
    48 0.85 0.50
    49 0.18 0.16
    50 0.06 0.31
    51 2.13
    52 5.57E-03 0.01
    53 7.72E-04 3.45E-03
    54 0.08 0.30
    55 0.11 0.23
    56 3.12 3.59
    57 0.22 0.27
    58 0.06 0.10
    59 0.01 0.02
    60 0.14 0.14
    61 0.70 0.51
    62 2.28 4.12
    63 0.12
    64 0.29
    65 3.70
    66 0.03
    67 0.35
    68 0.56
    69 0.89
    70 0.11
    71 1.74
    72 0.85
    73 0.15
    74 5.77
    75 3.24E-03
    76 0.02
    77 3.26
    78 1.92
    79 1.81E-03
    80 8.75E-03
    81 0.27
    82 0.0038
    83 0.02
    84 2.11
    85 1.65E-03
    86 4.16E-03
    87 3.68E-03
    88 9.82E-03
    89 0.05
    90 0.01
    91 0.06
    92 0.02
    93 0.08
    94 9.24E-03
    95 0.20
    96 1.18
    97 4.64
    98 0.03
    99 0.09
    100 0.09
    101 0.01
    102 0.21
    103 1.76
    104 0.10
    105 0.19
    106 8.81E-03
    107 1.86
    108 0.25
    109 0.41
    110 0.04
    111 0.21
    112 0.03
    113 0.40
    114 0.16
    115 0.35
    116 2.34
    117 0.01
    118 4.76E-03
    119 5.19E-03
    120 0.03
    121 2.59E-03
    122 3.47E-03
    123 0.02
    124 5.18E-03
    125 5.92E-03
    126 0.01 0.02
    127 0.08 0.13
    128 0.39
    129 9.53E-03
    130 0.04
    131 0.05
    132 0.05
    133 6.45E-03
    134 0.03
    135 0.02
    136 0.07
    137 5.24E-03
    138 6.24E-03
    139 1.98
    140 2.96
    141 0.43
    142 0.95
    143 0.15
    144 0.01
    145 0.08
    146 0.01
    147 0.01
    148 0.04
    149 0.06
    150 0.06 0.04
    151 4.62
    152 0.77
    153 5.16E-03
    154 0.03
    155 0.04
    156 7.45E-03
    157 0.02
    158 0.03
    159 0.98
    160 0.19
    161 0.24
    162 1.27
    163 1.03
    164 5.40E-03
    165 0.01
    166 0.02
    167 0.04
    168 0.03
    169 4.55E-03
    170 5.68E-03
    171 0.02
    172 0.01
    173 0.01
    174 9.92E-03
    175 4.36E-03
    176 7.86E-03
    177 9.59E-03
    178 5.49E-03
    179 0.05
    180 0.23
    181 0.27
    182 0.05
    183 0.02
    184 0.01
    185 2.63E-03
    186 0.03
    187 0.02
    188 0.29
    189 0.48
    190 0.08
    191 5.79E-03
    192 7.82E-03
    193 0.07 0.03
    194 4.74E-03
    195 4.79E-03
    196 0.02
    197 0.01
    198 0.21
    199 0.06
    200 0.11
    201 4.46E-03
    202 0.01
    203 7.31E-03
    204 5.26E-03
    205 0.02
    206 0.60
    207 0.13
    208 0.05
    209 0.56
    210 0.21
    211 0.11 0.49
    212 0.20 1.27
    213 6.56E-03 0.01
    214 1.07E-03 2.36E-03
    215 0.12 1.28
    216 8.31E-04 8.35E-04
    217 0.01 0.06
    218 0.09 0.49
    219 0.01 0.08
    220 0.44 1.47
    221 6.56E-03 9.05E-03
    222 2.63E-03 0.01
    223 0.16 0.42
    224 0.44 0.64
    225 2.52E-03
    226 2.67E-03
    227 2.91E-03
    228 1.74E-03
    229 2.56E-03
    230 2.14E-03
    231 2.13E-03 2.73E-03
    232 0.66
    233 0.81
    234 9.37
    235 0.79
    236 2.14
    237 1.29
    238 0.75
    239 3.86
    240 2.23
    241 0.02
    242 4.72E-03
    243 7.60E-04
    244 9.30E-03
    245 0.18
    246 1.22
    247 2.76
    248 5.07
    249 0.14
    250 0.93
    251 0.09
    252 1.23
    253 2.49
    254 6.07
    255 0.03
    256 4.18
    257 2.73E-03
    258 0.09
    259 2.44E-03
    260 6.48E-03
    261 4.31
    262 0.19
    263 7.97E-03
    264 2.61E-03
    266 4.49
    267 1.46
    268 0.83
    269 0.25
    270 1.83
    271 1.01
    272 2.72
    273 0.18
    274 0.46
    275 0.50
    276 0.78
    277 0.16
    278 1.31E-03
    279 5.05
    280 2.39
    281 1.45
    282 8.20E-03
    283 0.01
    284 2.09
    285 2.28E-03
    286 0.11
    287 4.47E-03
    288 9.12
    289 1.21
    290 0.05 0.03
    291 1.83 0.09
    292 4.03E-03
    295 0.30
    296 0.18
    297 0.01
    298 0.08
    299 0.05 0.02
    300 0.18
    301 7.87E-03 2.85E-03
    302 5.53E-03 3.26E-03
    303 0.28 0.05
    304 0.07
    305 0.006
    306 0.04
    307 0.04
    308 0.27
    309 0.004
    315 7.77
    316 7.72
    317 0.05 0.03
    318 0.12
    319 0.02 0.02
    320 4.85E-03
    321 0.61
    322 0.22 0.06
    323 0.54
    324 0.16
    325 0.09
    326 1.33
    327 0.26
    328 0.39
    329 4.03E-03
    330 0.02
    331 0.16
    332 0.11 0.08
    333 0.30
    334 0.02
    335 1.08
    336 0.34
    337 0.41
    338 0.49
    339 0.16
    340 0.04 0.03
    341 8.45E-04 1.73E-03
    342 0.17
    343 0.23
    344 0.05 0.03
    345 0.82
    346 0.09
    347 5.26
    348 0.01 0.01
    349 0.13 7.49E-03
    350 0.25
    351 0.35
    352 0.22 0.09
    353 2.37E-03 5.10E-03
    354 0.12
    355 3.29E-03 2.37E-03
    356 4.06E-03
    357 0.32 0.04
    358 0.35 0.02
    359 0.55
    360 0.02
    361 0.22 0.11
    362 5.49
    363 0.90
    364 4.67
    365 5.06
    366 5.01
    367 0.01 0.02
    368 2.50
    369 0.52
    370 0.07 0.05
    371 3.74
    372 1.94
    373 4.00 3.34
    374 6.84
    375 4.74
    376 2.15E-03
    377 1.68E-03
    378 0.07 0.06
    379 0.03 0.02
    380 0.07 0.05
    381 0.11
    382 0.35 0.50
    383 0.13 0.07
    384 1.89 1.64
    385 0.20
    386 0.04
    387 2.23
    388 10.00
    389 0.62
    390 1.59
    391 0.28
    392 0.01
    393 2.07E-03
    394 7.90E-03
    395 0.07
    396 6.07E-03
    397 0.01
    398 9.69E-03
    399 0.02
    400 5.35E-03
    401 1.18
    402 4.83
    403 2.32E-03
    404 2.56
    405 1.23
    406 7.59E-03
    407 3.11
    408 0.01
    409 0.11
    410 0.05
    411 0.05
    412 0.06
    413 1.96
    414 8.45E-04 1.73E-03
    415 0.13
    416 0.10
    417 1.89E-03
    418 4.63E-03
    419 5.08E-03
    420 5.25
    421 3.30
    422 1.48
    423 0.02
    424 5.27E-03
    425 0.01
    426 8.85E-03
    427 1.61E-03
    428 1.84E-03
    429 5.55E-03
    430 6.06E-04
    431 3.76E-03
    432 1.82E-03
    433 1.97E-03
    434 3.70E-03
    435 3.00E-03
    436 1.16E-03
    437 3.13E-03
    438 1.67E-03
    439 0.01
    440 1.55E-03
    441 1.14E-03
    442 2.23E-03
    443 0.01
    444 3.21E-03
    445 0.05
    446 2.45E-03
    447 0.06
    448 1.56E-03
    449 1.41E-03
    450 5.47E-03
    451 1.74E-03
    452 6.61E-04
    453 9.90E-03
    454 2.35E-03
    455 0.51
    456 8.63E-04
    457 0.37
    458 0.14
    459 7.09E-03
    460 2.40E-03
    461 4.24E-03
    462 1.11E-03
    463 0.02
    464 0.79
    465 0.20
    466 1.74
    467 0.01
    468 0.08
    469 0.72
    470 0.19
    471 0.04
    472 9.13E-03 0.01
    473 0.06 0.07
    474 0.09
    475 0.05
    476 0.14
    477 7.65E-03
    478 0.01
    479 3.80
    480 1.84
    481 1.84
    482 0.04 0.02
    483 7.33E-03 6.12E-03
    484 0.01 2.50E-03
    485 5.75E-03
    486 0.03
    487 1.05
    488 3.46E-03
    489 0.22
    491 0.13
    492 0.16
    493 0.12
    494 0.03
    495 0.05
    496 0.01
    497 0.23
    498 0.59
    499 1.26
    500 0.02
    501 0.32
    502 0.02 5.01E-03
    503 0.01 2.24E-03
    504 5.14E-03 4.00E-04
    505 0.04
    506 0.04
    507 2.87
    509 6.63
    510 1.38E-03
    511 8.10E-03
    512 0.05 2.88E-03
    513 0.01
    514 0.02 0.01
    515 4.22
    516 0.05
    517 0.07
    518 0.02
    519 6.91E-03
    520 4.87
    521 8.44E-03
    522 1.22
    523 5.52
    524 2.72
    525 0.09
    526 0.24
    527 0.04
    528 0.16
    529 0.39
    530 0.30
    531 0.02
    532 4.82E-03
    533 8.02E-03
    534 3.05E-03
    535 0.14
    536 0.07
    537 6.08E-03
    538 0.01
    539 0.0033
    540 0.01
    541 3.43
    542 0.76
    543 7.24
    544 1.74
    545 0.06

Claims (15)

  1. A compound of Formula (I)
    Figure imgb1517
     wherein:
    W is CR4 or N,
    V is CR5 or N, and
    Y is CR6 or N;
    Figure imgb1518
    is optionally substituted aryl or optionally substituted 5- to 7-membered monocyclic heteroaryl;
    R1 is COOH, optionally substituted heterocyclyl, -NHSO2R20,
    Figure imgb1519
     -CONHSO2R21, -CONHCOOR22 or -SO2NHCOR23;
    R2 and R3 are independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy or optionally substituted N(C1-C6 alkyl)2;
    R4, R5 and R6 are independently H, halogen, CN, OH, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy;
    R7 and R8 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted di-deutero-C1-C10-alkyl, optionally substituted C2-C10 alkynyl, optionally substituted 5- to 7-membered monocyclic heteroaryl, optionally substituted 8- to 10-membered bicyclic heteroaryl, optionally substituted aryl C1-C6 alkyl, arylsulfonyl, optionally substituted C2-C6 alkenyl, or optionally substituted C5-C8 cycloalkenyl,
    provided that only one of R7and R8 is H,
    or R7 and R8 are taken together with the nitrogen to which they are attached to form an optionally substituted 4- to 10-membered monocyclic or bicyclic heterocyclic ring, or an optionally substituted 5- to 7-membered monocyclic heteroaryl ring;
    R9 is optionally substituted aryl; optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted 5- to 7-membered monocyclic heterocyclo, optionally substituted 7- to 10-membered bicyclic heterocyclo, optionally substituted 5- to 7-membered monocyclic heteroaryl, optionally substituted 8- to 10-membered bicyclic heteroaryl, optionally substituted C1-C6 alkanoyloxy 5- to 7-membered monocyclic heteroaryl, R24CO-, optionally substituted C1-C6 alkoxy, optionally substituted aryloxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C5-C8 cycloalkenyl;
    R20 is optionally substituted C1-C6 alkyl, CH2CF3, CF3 or CF2CF3;
    R21 is optionally substituted C1-C6 alkyl or optionally substituted C3-C8 cycloalkyl;
    R22 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
    R23 is optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl;
    R24 is optionally substituted aryl-C1-C6-alkyl, optionally substituted C1-C6 alkylaryl, aryl-C1-C6-alkyl(hydroxy), or optionally substituted C1-C6 alkyl;
    and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
  2. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as defined in Claim 1 wherein:
    W is CR4;
    V is CR5;
    Y is CR6 or N;
    R4 is H or halo;
    R5 is H or halo; and
    R6 is H or halo.
  3. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as defined in Claim 1 wherein
    Figure imgb1520
    is phenyl or a 5- to 6-membered monocyclic heteroaryl.
  4. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as defined in Claim 3 wherein
    Figure imgb1521
    is:
    Figure imgb1522
    Figure imgb1523
  5. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as defined in Claim 1 wherein:
    R1 is COOH, optionally substituted heterocyclyl, -NHSO2R20,
    Figure imgb1524
     -CONHSO2R21 or -CONHCOOR22;
    R2 is H, halogen, optionally substituted C1-C6 alkyl or
    optionally substituted C1-C6 alkoxy; and
    R3 is H or C1-C6 alkyl.
  6. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as defined in Claim 5 wherein:
    R1 is COOH, optionally substituted heterocyclyl, -NHSO2CH3,
    Figure imgb1525
     or -CONHSO2R21;
    where R21 is C1-C6 alkyl, C3-C8 cycloalkyl or CF3;
    R2 is H, CH3, C2H5, CH3O, CF3O, F, or Cl; and
    R3 is H, CH3, or C2H5.
  7. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof as defined in Claim 1 wherein:
    R7 and R8 are independently optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkyl, optionally substituted di-deutero-C1-C6-alkyl, optionally substituted C1-C6-alkylphenyl-C1-C6-alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8-cycloalkyl-C1-C8-alkyl, optionally substituted C1-C6-alkoxy-C1-C6-alkyl, optionally substituted 5- to 6-membered monocyclic heteroaryl, optionally substituted 7- to 10-membered bicyclic heteroaryl, optionally substituted aryl C1-C6 alkyl, phenylsulfonyl, optionally substituted C2-C6 alkenyl, or 5- to 6-membered monocyclic heteroaryl-C1-C6-alkyl,
    or R7 and R8 are taken together with the nitrogen to which they are attached to form
    (a) a 7- to 10-membered bicyclic heterocyclic ring which is optionally substituted with a phenyl-C1-C6-alkyl group, or
    (b) a 5- to 7-membered monocyclic heterocyclic ring which is optionally substituted with 1 or 2 C1-C6 alkyl groups, phenyl, a C1-C6-alkyl-substituted 5- to 7-membered monocyclic heteroaryl, and/or 1 or 2 halo groups; or
    (c) a 5- to 7-membered monocyclic heteroaryl which is optionally substituted with a C1-C6 alkyl;
    R9 is optionally substituted aryl; optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkylaryl, optionally substituted C1-C6 alkoxyaryl, optionally substituted C3-C8 cycloalkyl C1-C6 alkyl, optionally substituted 5- to 7-membered monocyclic heterocyclo, optionally substituted 7- to 10-membered bicyclic heterocyclo, optionally substituted 5- to 6-membered monocyclic heteroaryl, optionally substituted 8- to 10-membered bicyclic heteroaryl, optionally substituted C1-C6 alkanoyloxy 5- to 7-membered monocyclic heteroaryl, optionally substituted aryloxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C5-C8 cycloalkenyl, C2-C6 alkynylaryl, C2-C6 alkynyloxyaryl, 5- to 6-membered heteroarylaryl, 5- or 6-membered heterocycloaryl, C3-C8 cycloalkylaryl or C1-C6 alkanoyl.
  8. A compound of Formula (II)
    Figure imgb1526
     wherein:
    Y is CR6 or N;
    Figure imgb1527
    is phenyl substituted with R1, and optionally substituted with R2 and/or R3 or
    Figure imgb1528
    is a 5- to 7-membered monocyclic heteroaryl substituted with R1, and optionally substituted with R2 and/or R3;
    R1 is COOH, optional substituted tetrazol-5-yl, -NHSO2R20,
    Figure imgb1529
     or -CONHSO2R21;
    R20 is C1-C6 alkyl or CF3;
    R21 is C1-C6 alkyl, C3-C8 cycloalkyl or CF3;
    R2 is H,C1-C6 alkyl, halo, optionally substituted C1-C6-alkoxy or N(C1-C6 alkyl)2,
    R3 is H, C1-C6 alkyl, C1-C6 alkoxy, or halo;
    R4 is H, halo or C1-C6 alkyl;
    R5 is H, halo or C1-C6 alkyl;
    R6 is H or halo;
    R7 and R8 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted C3-C8 cycloalkyl, phenylsulfonyl, dideutero-C1-C6-alkyl, optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl, optionally substituted aryl-C3-C6-alkyl, optionally substituted C2-C6 alkynyl, optionally substituted 5- to 7-membered monocyclic heterocyclo, optionally substituted 7- to 10-membered bicyclic heterocyclo, optionally substituted C1-C6-alkoxy-C1-C6-alkyl, 5- to 7-membered monocyclic heteroaryl-C1-C6-alkyl, C2-C6 alkenyl, or C5-C8 cycloalkenyl,
    provided that only one of R7 and R8 is H,
    and wherein the optional substituents on R7 and R8, where possible, are 1 or 2 groups independently selected from hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, halo, optionally substituted aryl, optionally substituted C3-C8 cycloalkyl, 5- to 7-membered monocyclic heteroaryl or 5- to 7-membered monocyclic heterocyclic;
    or R7 and R8 are taken together with the nitrogen to which they are attached to form an optionally substituted 5- to 7-membered monocyclic heterocyclo ring, an optionally substituted 7- to 10-membered bicyclic heterocyclo ring, an optionally substituted 5- to 7-membered monocyclic heteroaryl ring, an optionally substituted 5- to 7-membered monocyclic heteroaryl-substituted 5- to 7-membered monocyclic heterocyclo ring, or a C3-C8-cycloalkyl-C1-C6-alkyl-substituted 7- to 10-membered bicyclic heterocyclo ring;
    R9 is H, C1-C10 alkyl, aryl, optionally substituted phenyl, C1-C6 alkylphenyl, optinally substituted C1-C6 alkoxyphenyl, di-C1-C6-alkylphenyl, dihalo(C1-C6-alkyl)phenyl, C2-C6 alkynylphenyl, optionally substituted 5- to 7-membered monocyclic heteroaryl, 7- to 10-membered bicyclic heteroaryl, C3-C8 cycloalkyl, C3-C8-cycloalkyl-C1-C6-alkyl, C2-C6 alkynyloxyphenyl, C2-C6-alkynyl-C1-C6-alkoxyphenyl, 5- to 7-membered monocyclic heteroarylphenyl, di-C1-C6-alkylaminophenyl, C1-C6 alkylsulfonylaminophenyl, 5- to 7-membered monocyclic heterocyclophenyl, C3-C8 cycloalkyl optionally substituted phenyl, optionally substituted phenyl-C1-C6-alkylcarbonyl, phenyl-C1-C6-alkyl or C1-C6 alkylcarbonyl;
    and/or a pharmaceutically acceptable salt thereof, a tautomer thereof or stereoisomer thereof.
  9. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to Claim 1 wherein the IC50 in the HEK Human IDO-1 assay is < 10 nM.
  10. A pharmaceutical composition comprising one or more compounds and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof according to any of claims 1-9 and a pharmaceutically acceptable carrier or diluent.
  11. A compound and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 for use in the treatment of cancer, viral infections, depression, organ transplant rejection or an autoimmune disease.
  12. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof for the use in the treatment of claim 11, wherein said cancer is selected from cancer of the colon, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, cancer of the head and neck, lymphoma, leukemia and melanoma.
  13. A compound and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 for use in a method for the treatment of cancer, viral infections, depression, organ transplant rejection or an autoimmune disease, in a patient comprising administering to said patient a therapeutically effective amount of a compound and/or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1-9.
  14. The compound and/or stereoisomer, tautomer or pharmaceutically acceptable salt thereof for the use in the method according to Claim 13 further comprising administering to the patient a therapeutically effective amount of an anti-viral agent, a chemotherapeutic agent, an immunosuppressant, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy and/or a tyrosine kinase inhibitor prior to, simultaneously with or after administration of the compound.
  15. A compound and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof for use in a method of inhibiting activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-9.
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US20160200674A1 (en) 2016-07-14
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JP2016530283A (en) 2016-09-29
JP6371851B2 (en) 2018-08-08
CA2921199A1 (en) 2015-03-05
WO2015031295A1 (en) 2015-03-05
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EP3039020A1 (en) 2016-07-06
US9758492B2 (en) 2017-09-12

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